Cyclopropane compounds and pharmaceutical use thereof

ABSTRACT

The present invention provides a compound having aggrecanase inhibitory activity and MMP-13 inhibitory activity, and useful as a therapeutic agent for osteoarthritis, rheumatoid arthritis and the like, more specifically, a cyclopropane compound of formula (1): 
     
       
         
         
             
             
         
       
     
     wherein R 1  is —(CH 2 ) m —X—(CH 2 ) n -A 1  etc., wherein m and n are the same or different and each is 0 to 6, X is a single bond, etc. and A 1  is a substituted C 3-14  hydrocarbon ring group, etc.; R 2  and R 3  are the same or different and each is a hydrogen atom, —(CH 2 ) p —X 1 —(CH 2 ) q -A 2 , etc., wherein p and q are the same or different and each is 0 to 6, X 1  is a single bond, etc. and A 2  is an optionally substituted C 3-14  hydrocarbon ring group, etc.; R 4  is —CO 2 R 9 , etc., wherein R 9  is a hydrogen atom, etc.; and R 20  and R 21  are the same or different and each is a hydrogen atom, —(CH 2 ) m12 —X 12 —(CH 2 ) m12 —R 30  etc., wherein m12 and m12 are the same or different and each is 0 to 6, X 12  is a single bond, etc. and R 30  is a hydrogen atom, etc.; or a prodrug thereof or a pharmaceutically acceptable salt thereof.

This Application claims benefit of priority of U.S. provisionalApplication No. 60/529,116, filed Dec. 15, 2003, the contents of whichare hereby incorporated by reference.

The present invention relates to a novel cyclopropane compound. Infurther detail, the present invention relates to a cyclopropane compoundor a pharmaceutically acceptable salt thereof having an aggrecanaseinhibitory activity or matrix metalloproteinase (MMP) inhibitoryactivity, a pharmaceutical composition which comprises this compound anda pharmaceutical use thereof.

Aggrecan is a main proteoglycan in cartilage, and decomposition of itscore protein by protease is one of the early signs of a joint disorderassociated with arthrodial cartilage destruction, such as rheumatoidarthritis and osteoarthritis. This process of decomposition leading tothe cartilage destruction begins with the disappearance of aggrecan onthe surface of cartilage, and progresses to the decomposition ofcollagen type II fiber. MMPs (Matrix metalloproteinases) that cleave Asn341-Phe 342 and aggrecanase that cleaves Glu 373-Ala 374 are known asenzymes involved in this decomposition of aggrecan, and both aremetal-proteases having zinc in the catalytic active center. The latterwas determined to be ADAMTS (A Disintegrin and Metalloproteinase withThrombospondin Motifs) in 1999. ADAMTS 1 to 20 have been identified sofar, and ADAMTS 4 and 5 correspond to aggrecanase-1 and aggrecanase-2,respectively. Conventionally, MMP have been considered to mainly causecartilage destruction, but many reports have documented that theaggrecan fragments found in the joint of osteoarthritis (OA) patientsare predominantly the fragments cleaved by aggrecanases. Thus,aggrecanase is also considered to be a significant vicious factor forthese disease states.

At present, conservative treatments and surgical treatments areavailable for treating OA. The conservative therapy includes body weightcontrol, exercise therapy, physical therapy, drug therapy(administration of anti-inflammatory drug), hyperthermia, and the like.It is a general practice to inject hyaluronic acid into the joint in thecourse of these treatments to smoothen movement of the joint.

When improvement of conditions by the conservative treatments such asdrug therapy, physical therapy, etc., is not achieved, a surgicaltreatment is performed. When the joint is highly deformed and causes astrong pain, an arthroplasty for embedding an artificial joint isperformed as the final option. However, artificial joints have a life ofonly about 15 to 20 years, after which the QOL (Quality of Life) of thepatient deteriorates.

At present, no drug that suppresses enzyme involved in cartilagedestruction is available for OA treatment. When no improvement is madeby a conservative treatment, cartilage destruction progresses and asurgical treatment will be required. Therefore, prevention of cartilagedestruction before reaching the stage requiring a surgical treatment isimportant. A drug that inhibits aggrecanases involved in the destructionof cartilage is acknowledged to be an anti-OA drug having a sufficientcartilage destruction inhibitory activity. Without a surgical treatment,and moreover, such drug is expected to improve the QOL of patients.

Aggrecanase inhibitors have been developed as shown in the reports byDuPont (WO99/0900), Pfizer (JP-A-2001-114765) and the like, in whichpoor oral availability is a concern.

In addition, the MMP inhibitors under development include a compoundthat causes systemic connective tissue toxicity due to nonselectivecollagenase inhibition. It is proposed that the cause thereof issuppression of turnover of normal connective tissue collagen due toinhibition of collagenase-1 (MMP-1). It is clear, therefore, that theconventional products are not entirely satisfactory from the aspects ofeffective inhibition and occurrence of side effects.

The compound of the present invention possesses improved oralavailability and shows strong aggrecanase inhibitory activity. While thecompound is free of an MMP-L inhibitory activity, it also has selectiveinhibitory activity of MMP-13, involved in joint destruction. Therefore,the compound is expected to suppress progress of joint diseases withoutcausing side effects.

In addition, expressed in glioma, aggrecanase is suggested to be alsoinvolved in metastasis or tissue infiltration of tumor cells, like MMP,and in view of the current development of MMP inhibitor as anantimetastatic drug, the compound of the present invention having aninhibitory activity on both aggrecanase and MMP is expected to be ahighly effective antitumor agent.

In bone metabolism, MMP suppresses decomposition of bone matrix and hasa major part in bone resorption. In respiratory diseases, protease playsa key role in the course of destruction and remodeling of lungstructure. MMP that uses an extracellular matrix (ECM), which is anarchitectural component of the protease, as a substrate is considered tobe an important factor. Therefore, the compound of the present inventionhaving MMP inhibitory activity is expected to be applicable to the boneresorption disorders and lung diseases, in which MMP is involved.

Various reports on compounds aiming at therapy of disorders such as OA,rheumatoid arthritis and the like by inhibition of aggrecanase have beenpublished recently.

For example, JP-A-2002-284686 discloses a sulfonamide derivative havingMMP-13 inhibitory activity and aggrecanase inhibitory activity. However,this publication does not include the compound having a structure, suchas the structure of the compound of the present invention, or adisclosure suggestive thereof

JP-A-2001-114765 discloses a hydroxamic acid derivative represented bythe following formula:

wherein X is carbon atom or nitrogen atom; R¹ and R² are eachindependently hydrogen atom, hydroxy or methyl, and at least one of R¹and R² is methyl; R³ and R⁴ are each independently hydrogen atom,hydroxy or methyl, or R³ and R⁴ may be taken together to form carbonylgroup; R⁵ and R⁶ are each independently hydrogen atom, halogen, cyano,methyl or ethyl; with the proviso that when X is carbon atom, R⁷ and R⁸are both hydrogen atom and at least one of R¹, R², R³ and R⁴ is hydroxy;when X is carbon atom and R⁵ is para-halo, at least one of R⁶, R³ and R⁴is not hydrogen atom; when X is nitrogen atom, R⁸ is not present and R⁷is hydrogen atom or the group of the formula:

wherein Y is —CH₂—NH₂ or —NH—CH₃; when X is nitrogen atom and R⁷ is H,R³ and R⁴ may be taken together to form carbonyl group, which hasaggrecanase inhibitory activity. However, the compound of thispublication has a piperidine ring or piperazine ring havingsubstituent(s) as a skeletal structure. This publication does notinclude the compound having a cyclopropane structure, such as thestructure of the compound of the present invention, or a disclosuresuggestive thereof.

WO03/053915 discloses a cyclopropane derivative represented by theformula:

wherein M is —(C(R³⁰)(R⁴⁰))m- wherein m is 1 to 6; T is R²¹-substitutedalkyl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl,heterocycloalkenyl, aryl group, heteroaryl group, —OR³—C(O)R⁴, —C(O)OR³,—C(O)NR²⁴R²⁵, —C(O)NR²⁴OR³, —C(O)SR³, —NR²⁴R²⁵, —NR²⁵C(O)R⁴,—NR²⁵C(O)OR³, —NR²⁵C(O)NR²⁴R²⁵, —NR²⁵C(O)NR²⁴OR³, —SR³, —S(O)NR²⁴R²⁵,—S(O)_(x)NR²⁵OR³, etc.; V is alkyl group, R²¹-substituted alkyl group,cycloalkyl group, heterocycloalkyl group, cycloalkenyl,heterocycloalkenyl, aryl group, heteroaryl group, —OR³, —C(O)R⁴,—(CR²³R²⁴)_(n1)C(O)OR³, —C(O)NR²⁴R²⁵, —(CR²³R²⁴)_(n1)C(O)NR²⁵OR³,—C(O)SR³, —NR²⁴R²⁵, —NR²⁵C(O)R⁴, —NR²⁵C(O)OR³, —NR²⁵C(O)NR²⁴R²⁵,—NR²⁵C(O)NR²⁴R³, —SR³, —S(O)xNR²⁴R²⁵, —S(O)xNR²⁵OR³, etc.; W is acovalent bond, —(C(R³)(R⁴))_(n2)—, —O—, —S—, etc.; X is alkylene,cycloalkylene, heterocycloalkylene, arylene, heteroarylene, —

C≡C—, etc.; U is a covalent bond, —(C(R³)(R⁴))p-, —Y—(C(R³)(R⁴))q-,—(C(R³)(R⁴))t-Y—, —Y—, etc.; Y is —O—, —S(O)x-, etc.; n is 0 to 2; R¹ isalkyl group, R²¹-substituted alkyl group, cycloalkyl group,heterocycloalkyl group, cycloalkenyl, heterocycloalkenyl, aryl group,heteroaryl group, etc.; R², R⁴ and R⁵ are each independently hydrogenatom, halo, alkyl group, etc.; R³ is hydrogen atom, alkyl group,R²²-substituted alkyl group, etc.; R²³ is hydrogen atom, hydroxyl, halo,etc.; R²⁴ is hydrogen atom or alkyl; R²⁵ is hydrogen atom, hydroxyl,alkyl group, etc.; R³⁰ is hydrogen atom, etc.; R⁴⁰ is hydrogen atom,etc.; with the proviso that at least one of V and T is —C(O)N(R³)(OR⁴),—C(O)OR³ or —C(O)NR²⁴R²⁵. However, the compound of the formula disclosedin this publication is structurally different from the compound of thepresent invention. This publication does not include a compound having astructure of the compound of the present invention, or a disclosuresuggestive thereof.

DISCLOSURE OF INVENTION

The present invention provides a compound having superior aggrecanaseinhibitory activity and MMP inhibitory activity (particularly, MMP-13inhibitory activity), and useful as a prophylactic or therapeutic agentfor osteoarthritis, a prophylactic or therapeutic agent for rheumatoidarthritis, a prophylactic or therapeutic agent for a disorder such asjoint injury, reactive arthritis, bone resorption disorder, cancer,asthma, allergic reaction, chronic pulmonary emphysema, fibroid lung,acute respiratory distress (ARDS), lung infection, interstitialpneumonia, etc. compound.

Some embodiments of the present invention provide an aggrecanaseinhibitor, an MMP inhibitor, a prophylactic or therapeutic agent forosteoarthritis and a prophylactic or therapeutic agent for rheumatoidarthritis.

The present inventors have conducted intensive studies to obtain theabove objects and found a cyclopropane compound represented by thefollowing formula (1) has superior aggrecanase inhibitory activity andMMP-13 inhibitory activity, and useful as an aggrecanase inhibitor, anMMP inhibitor, a prophylactic or therapeutic agent for osteoarthritisand a prophylactic or therapeutic agent for rheumatoid arthritis, basedon which findings the present invention has been completed.

Accordingly, the present invention relates the compounds [1] to [34]shown below and pharmaceutical use thereof.

[1] A cyclopropane compound of formula (1):

whereinR¹ is selected from(1) a substituted C₁₋₆ alkyl groupand(2) —(CH₂)_(m)—X—(CH₂)_(n)-A¹,wherein

m and n are the same or different and each is selected from 0 and aninteger ranging from 1 to 61

X is a linker selected from the following group A, group A:

(a) a single bond,(b) a C₁₋₆ alkylene group,(c) a C₂₋₆ alkenylene group,(d) a C₂₋₆ alkynylene group,

(e) —O—, (f) —N(R⁵)—, (g) —S(O)_(m1)—, (h) —CO—, (i) —COO—, (j) —OCO—,(k) —CON(R⁵)—, (l) —N(R⁵)CO—, (m) —SO₂N(R⁵)—, (n) —N(R⁵)SO₂—, (o)—N(R⁵)CON(R⁶)— (p) —N(R⁵)SO₂N(R⁶)—, (q) —OCON(R⁵)—, (r) —N(R⁵)COO—

and(s) —S(O)_(m1)—(CH₂)_(n1)—CO—;

wherein

-   -   R⁵ and R⁶ are the same or different and each is selected from a        hydrogen atom, a C₁₋₆ alkyl group optionally substituted by        halogen atoms or hydroxyl groups, a C₃₋₁₄ hydrocarbon ring group        and a heterocyclic group,    -   m1 is selected from 0 and an integer ranging from 1 to 2 and    -   n1 is selected from an integer ranging from 1 to 2, and

A¹ is selected from a substituted C₃₋₁₄ hydrocarbon ring group and asubstituted heterocyclic group;

R² and R³ are the same or different and each is selected from (1)—(CH₂)_(p)—X₁—(CH₂)_(q)-A²,wherein

p and q are the same or different and each is selected from 0 and aninteger ranging from 1 to 6,

X₁ is a linker selected from the above-mentioned group A and

A² is selected from an optionally substituted C₃₋₁₄ hydrocarbon ringgroup and an optionally substituted heterocyclic group,

and(2) —(CH₂)_(m8)—X₈(CH₂)_(n8)—R²⁷,wherein

m8 and n8 are the same or different and each is selected from 0 and aninteger ranging from 1 to 6,

X₈ is a linker selected from the above-mentioned group A and

R²⁷ is a substituent selected from the following group B,

group B:(a) a hydrogen atom,(b) a halogen atom,(c) a hydroxyl group,(d) a nitro group,(e) a cyano group,(f) a carboxyl group,(g) an amino group,(h) an amido group,(i) a C₂₋₆ acyl group,(j) a halogenated C₁₋₆ alkyl group,(k) a C₁₋₆ alkyl group optionally substituted by hydroxyl groups,(l) a C₂₋₆ alkenyl group optionally substituted by halogen atoms,(m) a C₂₋₆ alkynyl group,(n) a C₁₋₆ alkoxy group optionally substituted by hydroxyl groups,(o) a C₁₋₆ alkoxy-C₁₋₆ alkyl group,(p) a C₁₋₆ alkoxy-carbonyl group,(q) a C₁₋₆ alkyl-aminocarbonyl group optionally substituted by halogenatoms,(r) a mono(C₁₋₆ alkyl)amino group,(s) a di(C₁₋₆ alkyl)amino group,(t) a C₁₋₆ alkyl-carbonylamino group optionally substituted by halogenatoms,(u) a C₁₋₆ alkylsulfonyl group and(v) a C₁₋₆ alkylsulfonylamino group;or A² and R²⁷ may be taken together to form an optionally substitutedfused ring group,or R² and R³ may be taken together with a carbon atom bonded thereto toform the following ring

wherein m13 is selected from an integer ranging from 1 to 6, providedthat R² and R³ are not hydrogen atoms at the same time;R⁴ is selected from

(1) —CO₂R⁹, (2) —C(O)NHOR⁹, (3) —C(O)NH—SO₂—R⁹, (4) —C(O)NHR⁹, (5) —SH,(6) —CH₂CO₂R⁹, (7) —C(O)R⁹, (8) —N(OH)COR⁹, (9) —SN₂H₂R⁹, (10) —SONHR⁹,(11) —CH₂CO₂H, (12) —PO(OH)₂, (13) —PO(OH)NHR⁹, (14) —CH₂SH, (15)—CH₂OH,

(16) —(CH₂)_(r1)—PO(OH)—(CH₂)_(r2)—R⁹,

(17) —NHR⁹ (18) —NH—NHR⁹

and(19) —(CH₂)_(r1)—R⁵⁰wherein

r1 and r2 are the same or different and each is selected from 0 and aninteger ranging from 1 to 6,

R⁹ is selected from

(1) a hydrogen atom,

(2) an optionally substituted C₁₋₁₀ alkyl group,

(3) an optionally substituted C₆₋₁₄ aryl-C₁₋₆ alkyl group and

(4) —(CH₂)_(m9)—X₉—(CH₂)_(n9)—R²⁸

wherein

-   -   m9 and n9 are the same or different and each is selected from 0        and an integer ranging from 1 to 6,    -   X₉ is a linker selected from the above-mentioned group A and    -   R²⁸ is a substituent selected from the following group C,        group C:        (a) a hydrogen atom,        (b) a halogen atom,        (c) a hydroxyl group,        (d) a nitro group,        (e) a cyano group,        (f) a carboxyl group,        (g) an amino group,        (h) an amido group,        (i) a C₂₋₆ acyl group,        (j) a halogenated C₁₋₆ alkyl group,        (k) a C₁₋₆ alkyl group optionally substituted by hydroxyl        groups,        (l) a C₂₋₆ (alkenyl group optionally substituted by halogen        atoms,        (m) a C₂₋₆ alkynyl group,        (n) a C₁₋₆ alkoxy group optionally substituted by hydroxyl        groups,        (o) a C₁₋₆ alkoxy-C₁₋₆ alkyl group,        (p) a C₁₋₆ alkoxy-carbonyl group,        (q) a C₁₋₆ alkyl-aminocarbonyl group optionally substituted by        halogen atoms,        (r) a mono(C₁₋₆ alkyl)amino group,        (s) a di(C₁₋₆ alkyl)amino group,        (t) a C₁₋₆ alkyl-carbonylamino group optionally substituted by        halogen atoms,        (u) a C₁₋₆ alkylsulfonyl group,        (v) a C₁₋₆ alkylsulfonylamino group,        (w) a C₃₋₁₄ hydrocarbon ring group optionally substituted by 1        to 5 substituent(s) selected from the above-mentioned group B        and        (x) a heterocyclic group optionally substituted by 1 to 5        substituent(s) selected from the above-mentioned group B, and

R⁵⁰ is selected from an optionally substituted C₃₋₁₄ hydrocarbon ringgroup and an optionally substituted heterocyclic group;

or R⁹ of —C(O)NHR⁹, A² and the cyclopropane ring may be taken togetherto form an optionally further substituted fused ring;R²⁰ and R²¹ are the same or different and each is selected from(1) —(CH₂)_(m10)—X₁₀—(CH₂)_(n10)-A³,wherein

m10 and n10 are the same or different and each is selected from 0 and aninteger ranging from 1 to 6,

X₁₀ is a linker selected from the above-mentioned group A and

A³ is selected from an optionally substituted C₃₋₁₄ hydrocarbon ringgroup and an optionally substituted heterocyclic group,

and(2) —(CH₂)_(m12)—X₁₂—(CH₂)_(n12)—R³⁰,wherein

m12 and n12 are the same or different and each is selected from 0 and aninteger ranging from 1 to 6,

X₁₂ is a linker selected from the above-mentioned group A and

R³⁰ is a substituent selected from the above-mentioned group B;

or A², R³⁰ and the cyclopropane ring may be taken together to form aoptionally further substituted fused ring,or R⁹ of —CO₂R⁹, R²⁰ and the cyclopropane ring may be taken together toform an optionally further substituted fused ring, or R²⁰ and R²¹ may betaken together with a carbon atom bonded thereto to form the followingring

wherein m14 is selected from an integer ranging from 1 to 6; or aprodrug thereof or a pharmaceutically acceptable salt thereof[hereinafter sometimes referred to as compound (1)];[2] The compound of [1] above, wherein the substituted C₃₋₁₄ hydrocarbonring group or the substituted heterocyclic group in A¹ is a group of thefollowing formula:

wherein

ring A¹⁰ is selected from a C₃₋₁₄ hydrocarbon ring group and aheterocyclic group,

r is selected from an integer ranging from 1 to 4,

R²² is —(CH₂)_(m4)—X₄—(CH₂)_(n4)—R²⁴,

-   -   wherein        -   m4 and n4 are the same or different and each is selected            from 0 and an integer ranging from 1 to 6,        -   X₄ is a linker selected from the above-mentioned group A            and,        -   R²⁴ is a substituent selected from the above-mentioned group            B,

wherein the substituents R²² are the same or different when r is aninteger selected from the range of 2 to 4,

and

R²³ is

wherein

-   -   m5 and n5 are the same or different and each is selected from 0        and an integer ranging from 1 to 6,    -   X₅ is a linker selected from the above-mentioned group A and    -   ring A¹¹ is selected from a C₃₋₁₄ hydrocarbon ring group and a        heterocyclic group, and the ring All is optionally substituted        by 1 to 5 groups of the formula “—(CH₂)_(m6)—X₆—(CH₂)_(n6)—R²⁵”,        which are the same or different,    -   wherein        -   m6 and n6 are the same or different and each is selected            from 0 and an integer ranging from 1 to 6,        -   X₆ is a linker selected from the above-mentioned group A and        -   R²⁵ is a substituent selected from the above-mentioned group            C;            or the ring A¹⁰ and the ring A¹¹ may be taken together with            a substituent thereof to form an optionally substituted            fused ring group;            the optionally substituted C₃₋₁₄ hydrocarbon ring group or            the optionally substituted heterocyclic group in A² is a            group of the following formula:

wherein

ring A¹² is selected from a C₃₋₁₄ hydrocarbon ring group and aheterocyclic group, and the ring A¹² is optionally substituted by 1 to 5groups of the formula “—(CH₂)_(m7)—X₇—(CH₂)_(n7)—R²⁶”, which are thesame or different,

wherein

-   -   m7 and n7 are the same or different and each is selected from 0        and an integer ranging from 1 to 6,    -   X₇ is a linker selected from the above-mentioned group A and    -   R²⁶ is a substituent selected from the above-mentioned group C;        or R²⁶ may be linked with R²⁷, together with ring A¹² to form an        optionally substituted fused ring group,        or R²⁶ may be linked with R⁹ of —C(O)NHR⁹ or R³⁰, together with        the ring A¹² and the cyclopropane ring to form an optionally        further substituted fused ring;        the optionally substituted C₃₋₁₄ hydrocarbon ring group or the        optionally substituted heterocyclic group in A³ is a group of        the following formula:

wherein

ring A¹³ is selected from a C₃₋₁₄ hydrocarbon ring group and aheterocyclic group, and the ring A¹³ is optionally substituted by 1 to 5groups of the formula “(CH₂)_(m11)—X₁₁—(CH₂)_(n11)—R²⁹”, which are thesame or different,

wherein

-   -   m11 and n11 are the same or different and each is selected from        0 and an integer ranging from 1 to 6,    -   X₁₁ is a linker selected from the above-mentioned group A and    -   R²⁹ is a substituent selected from the above-mentioned group C;        or a prodrug thereof or a pharmaceutically acceptable salt        thereof;        [3] The compound of [2] above, wherein R¹ is        —(CH₂)_(m)—X—(CH₂)_(n)-A¹; or a prodrug thereof or a        pharmaceutically acceptable salt thereof;        [4] The compound of [3] above, wherein m and n are 0 and X is a        single bond; or a prodrug thereof or a pharmaceutically        acceptable salt thereof;        [5] The compound of [4], wherein A¹ is

R²³ is

m5 and n5 are 0 and X₅ is a single bond; or a prodrug thereof or apharmaceutically acceptable salt thereof;[6] The compound of [5] above, wherein R⁴ is selected from —CO₂R⁹ and—C(O)NHOR⁹; or a prodrug thereof or a pharmaceutically acceptable saltthereof;[7] The compound of [6] above, wherein R⁹ is a hydrogen atom; or aprodrug thereof or a pharmaceutically acceptable salt thereof;[8] The compound of [7] above, wherein R² is —(CH₂)_(p)—X₁—(CH₂)_(q)-A²;or a prodrug thereof or a pharmaceutically acceptable salt thereof;[9] The compound of [8] above, wherein p and q are 0 and X₁ is a singlebond; or a prodrug thereof or a pharmaceutically acceptable saltthereof;[10] The compound of [1] above, which is selected from the groupconsisting of

-   4-{5-((1S,2R)-1-Carboxy-2-phenyl-cyclopropylsulfamoyl)-thiophen-2-yl}-3,6-dihydro-2H-pyridine-1-carboxylic    acid tert-butyl ester,-   (1S,2R)-2-Phenyl-1-{5-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   4-{5-((1S,2R)-1-Carboxy-2-phenyl-cyclopropylsulfamoyl)-thiophen-2-yl}-3,6-dihydro-2H-pyridine-1-carboxylic    acid methyl ester,-   (1S,2R,3R)-1-{5-(4-Ethynyl-pyrazol-1-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-{4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,1aS*,8bS*)-1-{5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino}-1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid,-   (1S,2R,3R)-1-{5-[5-(1,1-Difluoro-ethyl)-isoxazol-3-yl]-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2R*,3R*)-2-Hydroxymethyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-(4-phenylcarbamoyl-piperazine-1-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(3-Amino-4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,1aS*,6aS*)-1-[4-(3,5-Dichloro-benzyloxy)-benzenesulfonylamino]-1,1a,6,6a-tetrahydro-cyclopropa[a]indene-1-carboxylic    acid hydroxyamide,-   (1R*,2S*)-1-{5-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[3-(4-Chloro-phenoxy)-azetidine-1-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-1-{5-(4-trifluoromethoxy-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{5-(3,4-Dichloro-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-1-{5-(4-trifluoromethyl-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-1-(5-p-tolyl-thiophene-2-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Fluoro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[2-(pyridin-3-ylmethoxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[2-(pyridin-2-ylmethoxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[2-(pyridin-3-yloxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[2-(2-hydroxy-2-methyl-propoxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Methyl-thiazol-2-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(6-Chloro-pyridin-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-1-{4-(3-trifluoromethyl-phenyl)-piperazine-1-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-1-{4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{4-(4-Chloro-3-trifluoromethyl-phenyl)-piperazine-1-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[4-(3-Chloro-phenyl)-piperazine-1-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(pyridin-3-ylaminomethyl)-phenyl]-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(6-Methoxy-pyridazin-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(5′-Cyano-[2,2′]bithiophenyl-5-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Hydroxy-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Benzyloxy-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(methyl-pyridin-3-ylmethyl-amino)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Benzyl-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(5′-Methyl-[2,2′]bithiophenyl-5-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(4′-methyl-biphenyl-2-yl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-cyclohexyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(2-hydroxy-2-methyl-propoxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Phenyl-1-{5-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Pentafluoroethyl-[1,2,4]oxadiazol-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-vinyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(4-oxo-4H-benzo[d][1,2,3]triazin-3-ylmethyl)-cyclopropanecarboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-ethyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[2-(2-dimethylamino-ethoxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(2-Methyl-thiazol-4-yl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Methyl-[1,2,4]oxadiazol-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-phenoxymethyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[2-(2-tert-Butylamino-ethoxy)-phenyl]-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(2-Methyl-thiazol-5-yl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{5-(5-Chloro-pyridin-2-yl)-thiophene-2-sulfonylamino}-2-(3-pyrazol-1-ylmethyl-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{5-(5-Chloro-pyridin-2-yl)-thiophene-2-sulfonylamino}-2-(3-methoxymethyl-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-cyclobutyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-isopropyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Phenyl-1-{5-(4-trifluoromethyl-thiazol-2-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-cyclopentyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-tert-Butyl-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(2-hydroxymethyl-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{4-(4-Methoxy-phenyl)-piperazine-1-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Hydroxy-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(5-Acetyl-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[4-(4-Fluoro-phenyl)-piperazine-1-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)—2-Phenyl-1-{4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-{3-[(2-methoxy-ethyl)-methyl-carbamoyl]-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-pyridin-3-yl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-{2-[(2-methoxy-ethyl)-methyl-carbamoyl]-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[2-(2-hydroxy-ethylcarbamoyl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(morpholine-4-carbonyl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(2-hydroxy-ethylcarbamoyl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[2-(morpholine-4-carbonyl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[2-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{5-(2-Methyl-oxazol-5-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4-Acetyl-benzenesulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(5-Benzenesulfonyl-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(5-Chloro-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-1-(thiophene-2-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-[5-(1,1-Difluoro-ethyl)-isoxazol-3-yl]-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Methyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[S-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(4-methyl-thiazol-2-yl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{5-(2-Methyl-oxazol-4-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{5-(5-Chloro-2-methyl-oxazol-4-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(2-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-phenyl)-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Phenyl-1-{5-(5-propyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(2-morpholin-4-ylmethyl-phenyl)-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Ethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-1-(5-propylcarbamoyl-thiophene-2-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(5-Isopropylcarbamoyl-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(5-Cyclopentylcarbamoyl-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-1-(5-phenylcarbamoyl-thiophene-2-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-1-{(5-(3,3,3-trifluoro-propylcarbamoyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Fluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Difluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(7-Bromo-9H-fluorene-2-sulfonylamino)-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(5′-Difluoromethyl-[2,2′]bithiophenyl-5-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   5-((1R*,2S*)-1-Carboxy-2-phenyl-cyclopropylsulfamoyl)-thiophene-2-carboxylic    acid,-   (1R*,2S*)-1-(5-Ethylcarbamoyl-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(5-Cyclopropylcarbamoyl-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-1-{5-(2,2,2-trifluoro-ethylcarbamoyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-[5-(1,1-Difluoro-ethyl)-isoxazol-3-yl]-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[3-(2-Acetoxy-ethyl)-phenyl]—{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(2-hydroxy-ethyl)-phenyl]-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Methoxymethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Pentafluoroethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-1-{5-(5-pentafluoroethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(5-Benzo[b]thiophen-2-yl-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Phenyl-1-{5-(5-phenyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Fluoromethyl-[1,2,4]thiadiazol-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-1-(5-propionyl-thiophene-2-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(5-Butyryl-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(5-Benzo[b]thiophen-3-yl-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Difluoromethyl-isothiazol-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Fluoromethyl-isothiazol-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Fluoromethyl-isothiazol-3-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(5-Benzofuran-2-yl-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-isopropyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-[5-(1,1-Difluoro-ethyl)-isothiazol-3-yl]-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-1-(1,3,4,9-tetrahydro-beta-carboline-2-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-1-(3-phenyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-7-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-1-(2-phenyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{4-(4-Chloro-phenoxy)-piperidine-1-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-ethyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(3-Hydroxy-3-methyl-but-1-ynyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Chloro-pyridin-2-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(3,3-Dimethyl-but-1-ynyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(5-Pent-1-ynyl-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Phenyl-1-{5-(3-trifluoromethyl-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(5-Indolizin-2-yl-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-(3-Bromo-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[4-(5-Fluoromethyl-isoxazol-3-yl)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2S)-2-((R)-3-Benzyl-2-oxo-oxazolidin-5-yl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2S)-2-((S)-3-Benzyl-2-oxo-oxazolidin-5-yl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Phenyl-1-((E)-2-phenyl-ethenesulfonylamino)-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(7-Fluoro-9H-fluorene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(7-Chloro-9H-fluorene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4-Phenoxy-piperidine-1-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-1-{4-(4-trifluoromethyl-phenoxy)-piperidine-1-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{4-(4-Fluoro-phenoxy)-piperidine-1-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Ethyl-1-(7-fluoro-9H-fluorene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2,2-dimethyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-1-(4-phenyl-3,6-dihydro-2H-pyridine-1-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R,2S)-2-(3-Bromo-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[(E)-2-(4-Chloro-phenyl)-ethenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[4-(5-Difluoromethyl-isoxazol-3-yl)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[(E)-2-(3-Chloro-phenyl)-ethenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Phenyl-1-{5-(4,5,6,7-tetrahydro-benzo[d]isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{4-(5-Bromo-pyrimidin-2-yl)-piperazine-1-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(8-Chloro-3,4-dihydro-1H-pyrazino[1,2-a]indole-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4-Benzothiazol-2-yl-piperazine-1-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4-Benzyl-piperazine-1-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{4-(4-Chloro-benzoyl)-piperazine-1-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{4-(3-Chloro-benzoyl)-piperazine-1-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Phenyl-1-[(E)-2-(4-trifluoromethyl-phenyl)-ethenesulfonylamino]-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Phenyl-1-[(E)-2-(3-trifluoromethyl-phenyl)-ethenesulfonylamino]-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(2-Oxo-pyrrolidin-1-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(2-Oxo-piperidin-1-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(5-Amino-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(2-Cyclohexyl-2,3-dihydro-1H-isoindole-5-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(2-Bromo-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R,2S)-2-(2-Bromo-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-(3-Bromo-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-nitro-phenyl)-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Phenyl-1-{5-(3-trifluoromethyl-isoxazol-5-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-{3-[(pyridin-3-ylmethyl)-amino]-phenyl}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-(3-amino-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   3-{(1R,2S)-2-Carboxy-2-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropyl}-benzoic    acid,-   (1S,2R)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-dimethylamino-phenyl)-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(1-Acetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-(2-Bromo-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[2-(2-Carboxy-ethyl)-phenyl]-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[3-(2-Carboxy-ethyl)-phenyl]-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Carboxymethyl-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-hydroxymethyl-phenyl)-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(methyl-pyridin-3-ylmethyl-amino)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-3-{2-Carboxy-2-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-cyclopropyl}-benzoic    acid methyl ester,-   (1R*,2S*)-2-Phenyl-1-{4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonylmethyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{4-(4-Chloro-phenyl)-piperazine-1-sulfonylmethyl}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylmethyl]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-methoxycarbonylmethyl-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-dimethylcarbamoylmethyl-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(2-morpholin-4-yl-2-oxo-ethyl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-{3-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-phenyl}-cyclopropanecarboxylic    acid,-   (1R,2S)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-(2-Bromo-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[2-(2-morpholin-4-yl-2-oxo-ethyl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-{2-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-{2-Carboxy-2-{(5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropyl}-benzoic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-{3-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Nitro-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(4-methyl-piperazine-1-carbonyl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Amino-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-2-(4-Bromo-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(4-Bromo-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(2-dimethylcarbamoylmethyl-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-{2-Carboxy-2-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropyl}-benzoic    acid methyl ester,-   (1S,2R)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(2-hydroxymethyl-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Acetyl-1,2,3,4-tetrahydro-isoquinoline-4-spiro-2′-{1-[5-(4-chloro-phenyl)-hiophene-2-sulfonylamino]-1′-cyclopropanecarboxylic    acid},-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(2-methoxycarbonyl-ethyl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(3-morpholin-4-yl-3-oxo-propyl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-{3-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(3-oxo-3-thiomorpholin-4-yl-propyl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Carboxymethyl-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-{3-[(Pyridin-3-ylmethyl)-amino]-phenyl}-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[3-(Methyl-pyridin-3-ylmethyl-amino)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(2-dimethylcarbamoyl-phenyl)-cyclopropane    carboxylic acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[2-(4-methyl-piperazine-1-carbonyl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(2-tert-Butoxycarbonylamino-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1aR*,7bS*)-5-(4-Chloro-phenyl)-thiophene-2-sulfonic acid    (2-oxo-1,2,3,7b-tetrahydro-3-aza-cyclopropa[a]naphthalen-1a-yl)-amide,-   (1R*,2S*)-2-(3-Methoxycarbonylmethyl-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[3-(2-Morpholin-4-yl)-2-oxo-ethyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-{3-[2-(4-Methyl-piperazin-1-yl)-2-oxo-ethyl]-phenyl}-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-{3-[2-(4-Hydroxy-piperidin-1-yl)-2-oxo-ethyl]-phenyl}-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(3-dimethylamino-propionylamino)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-{3-[3-(4-hydroxy-piperidin-1-yl)-3-oxo-propyl]-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(4-Benzyloxy-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(4-hydroxymethyl-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-hydroxy-propyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Dimethylamino-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-hydroxymethyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[2-(3-Morpholin-4-yl-3-oxo-propyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[2-(2-Dimethylcarbamoyl-ethyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-{2-[3-(4-Methyl-piperazin-1-yl)-3-oxo-propyl]-phenyl}-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-{3-[(4-trans-Hydroxy-cyclohexylcarbamoyl)-methyl]-phenyl}-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[3-(3-Morpholin-4-yl-3-oxo-propyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-{3-[3-(4-Methyl-piperazin-1-yl)-3-oxo-propyl]-phenyl}-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[3-(3-Hydroxy-propyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*,3S*)-1-{5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-4-Methyl-piperazine-1-carboxylic acid    3-(3-{2-carboxy-2-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropyl}-phenyl)-propyl    ester,-   (1R*,2S*)-Morpholine-4-carboxylic acid    3-(3-{2-carboxy-2-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropyl}-phenyl)-propyl    ester,-   (1R*,2S*)-2-[2-(2-Hydroxy-ethyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-Methyl-pyrazol-1-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-Morpholine-4-carboxylic acid    2-(2-{2-carboxy-2-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropyl}-phenyl)-ethyl    ester,-   (1R*,2S*)-2-[2-(2-Morpholin-4-yl-2-oxo-ethyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R,2S)-1-(7-Fluoro-9H-fluorene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(4-morpholin-4-yl-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[4-(4-methyl-piperazin-1-yl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[4-(4-methyl-piperazin-1-yl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Hydroxy-propyl)-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-morpholin-4-yl-propyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-{3-[(Morpholine-4-carbonyl)-amino]-phenyl}-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-{3-[(morpholine-4-carbonyl)-amino]-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[2-(3-Hydroxy-propyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-Morpholine-4-carboxylic acid    3-(2-{2-carboxy-2-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropyl}-phenyl)-propyl    ester,-   (S)-2-Hydroxymethyl-pyrrolidine-1-carboxylic acid    3-(2-{(1R*,2S*)-2-carboxy-2-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropyl}-phenyl)-propyl    ester,-   (R)-3-Hydroxy-pyrrolidine-1-carboxylic acid    3-(2-{(1R*,2S*)-2-carboxy-2-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropyl}-phenyl)-propyl    ester,-   (1S,2R)-1-{5-(4-Methyl-piperidin-1-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Morpholin-4-yl-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[3-(Morpholine-4-carbonyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-{2-[(Morpholine-4-carbonyl)-amino]-ethyl}-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[3-(2-Morpholin-4-yl-acetylamino)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[(5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(2-morpholin-4-yl-acetylamino)-phenyl]-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2R*)-[(5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(2-hydroxy-ethyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Acetoxy-propyl)-2-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(4-Aminomethyl-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(4-Dimethylcarbamoyl-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[3-(Morpholine-4-sulfonylamino)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[3-(2-Hydroxy-ethyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(morpholine-4-sulfonylamino)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[3-(2-Carbamoyloxy-ethyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Acetoxy-propyl)-2-{4-[(2-methoxy-ethyl)-methyl-carbamoyl]-phenyl}-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Acetylamino-propyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-2-(˜3-pyrazol-1-yl-propyl)-cyclopropanecarboxylic    acid,-   (1R*,3S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2,2-dimethyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,3S*)-2,2-Dimethyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[3-(2-Oxo-pyrrolidin-1-yl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,1aS*,6aS*)-1-{5-(5-Trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-1,1a,6,6a-tetrahydro-cyclopropa[a]indene-1-carboxylic    acid,-   (1S,2R)-2-[4-(2-Carbamoyl-ethyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-[4-(3-Morpholin-4-yl-3-oxo-propyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-{4-[3-(4-Methyl-piperazin-1-yl)-3-oxo-propyl]-phenyl}-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-[4-(2-Methylcarbamoyl-ethyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-[4-(2-Dimethylcarbamoyl-ethyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Hydroxymethyl-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid;-   (1R*,2S*)-2-(3-tert-Butoxycarbonylamino-propyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Amino-propyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(7-Bromo-9H-fluorene-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-{5-(4-methyl-pyrazol-1-yl)-thiophene-2-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1R,2S,3S)-2-Methyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R,2S)-2-(4-Aminomethyl-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R,2S)-2-(4-Dimethylcarbamoylmethyl-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R,2S)-2-[4-(2-Morpholin-4-yl-2-oxo-ethyl)-phenyl]-1-{(5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R,2S)-2-(4-Carbamoylmethyl-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R,2S)-2-(4-Methylcarbamoylmethyl-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R,2S)-2-{4-[2-(4-Methyl-piperazin-1-yl)-2-oxo-ethyl]-phenyl}-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-2-(2-Carbamoyloxy-ethyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid amide,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}—cyclopropanecarboxylic    acid methylamide,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-cyclopentyloxycarbonylamino-propyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*,3S*)-2-Ethyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-[4-(2-Amino-ethyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R,2S)-2-[4-(2-Hydroxy-ethyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-[4-(3-Hydroxy-propyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(2-dimethylcarbamoyloxy-ethyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-[3-(4-Isopropyl-piperazin-1-ylmethyl)-phenyl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,1aS*,8bS*)1-{5-(5-Trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid,-   (1R*,2R*)-Morpholine-4-carboxylic acid    2-carboxy-1-phenyl-2-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropylmethyl    ester,-   (1S,2R)-1-[5-(4-Chloro-benzoyl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2R*)-2-(2-Isopropoxy-ethylcarbamoyloxymethyl)-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-2-Phenyl-2-{(R)-1-(tetrahydro-furan-2-yl)methylcarbamoyloxymethyl}-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-Piperidine-1-carboxylic acid    2-carboxy-1-phenyl-2-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropylmethyl    ester,-   (1R*,2R*)-2-(3-Methyl-isoxazol-5-yl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   5-(5-Trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonic acid-   ((1S*,5S*,6S*)-2-oxo-6-phenyl-3-oxa-bicyclo[3.1.0]hex-1-yl)-amide,-   (1R*,2R*)-2-(5-Methyl-isoxazol-3-yl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(5-Methyl-isoxazol-3-yl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-2-[5-(2-Hydroxy-ethyl)-isoxazol-3-yl]-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[5-(2-Hydroxy-ethyl)-isoxazol-3-yl]-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-2-(5-Hydroxymethyl-isoxazol-3-yl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(5-Hydroxymethyl-isoxazol-3-yl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-isobutyrylamino-propyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2R*)-2-Dimethylcarbamoyloxymethyl-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-2-Ethylcarbamoyloxymethyl-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Morpholin-4-ylmethyl-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid hydroxyamide,-   (1S,2R,3R)-1-[4-(2,4-Dichloro-benzyloxy)-benzenesulfonylamino]-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-[4-(2,4-Dichloro-benzyloxy)-benzenesulfonylamino]-2-methyl-3-phenyl-cyclopropanecarboxylic    acid hydroxyamide,-   (1R*,2R*,3S*)-1-{5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*,3S*)-2-Ethyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S*,2R*,3R*)-2-Ethyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-2-pyrrolidin-1-ylmethyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-2-piperidin-1-ylmethyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-2-Cyclopropylcarbamoyloxymethyl-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-2-{[(2-Hydroxy-ethyl)-methyl-carbamoyloxy]-methyl}-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-2-(2-Hydroxy-ethylcarbamoyloxymethyl)-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-4-Methyl-piperazine-1-carboxylic acid    2-carboxy-1-phenyl-2-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropylmethyl    ester,-   (1R*,2R*)-2-Carbamoyloxymethyl-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(2-dimethylamino-ethylsulfanylmethyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-{5-(3-trifluoromethyl-isoxazol-5-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(4-Fluoro-phenyl)-2-methyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-2-(4-Fluoro-phenyl)-2-methyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-morpholin-4-ylmethyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(4-Methyl-piperazin-1-ylmethyl)-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Diethylaminomethyl-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[(5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-((2R,6S)-2,6-dimethyl-morpholin-4-ylmethyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2R*)-1-[(5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(2-hydroxy-ethylsulfanylmethyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-imidazol-1-ylmethyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(2-hydroxy-ethoxymethyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-2-(propane-2-sulfonylmethyl)-cyclopropanecarboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-isopropylsulfanylmethyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,1aS*,7bS*)-1-{5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino}-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylic    acid,-   (1R*,1aS*,7bS*)-1-{5-(5-Trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-ethoxycarbonylmethylsulfanylmethyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(5-Difluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(3-Difluoromethyl-isoxazol-5-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,1aS*,7bS*)-1-[4-(2,4-Dichloro-benzyloxy)-benzenesulfonylamino]-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylic    acid,-   (1R*,2R*)-2-Benzyloxymethyl-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-dimethylcarbamoylmethylsulfanylmethyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2R*)-2-Carboxymethylsulfanylmethyl-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(2-morpholin-4-yl-2-oxo-ethylsulfanylmethyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,1aS*,7bS*)-1-[4-(2,4-Dichloro-benzyloxy)-benzenesulfonylamino]-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylic    acid hydroxyamide,-   (1R*,2S*)-2-Aminomethyl-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(2-oxo-oxazolidin-3-ylmethyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,1aS*,8bS*)-1-[4-(2,4-Dichloro-benzyloxy)-benzenesulfonylamino]-1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid,-   (1R*,1aS*,7bS*)-1-{5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino}-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylic    acid hydroxyamide,-   (1R*,1aS*,8bS*)-1-{5-(5-Chloro-pyridin-2-yl)-thiophene-2-sulfonylamino}-1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropan-[c]cycloheptene-1-carboxylic    acid,-   (1S,2R,3R)-1-{5-(5-Chloro-pyridin-2-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-{5-(4-methyl-imidazol-1-yl)-thiophene-2-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-2-{[(pyridine-2-carbonyl)-amino]-methyl}-cyclopropanecarboxylic    acid,-   (1R*,1aS*,8bS*)-1-{5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino}-1a,2,3,8b-tetrahydro-1H-4-oxa-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid,-   (1R*,1aS*,8bS*)-1-{5-(5-Trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-1a,2,3,8b-tetrahydro-1H-4-oxa-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid,-   (1S,2R)-2-Phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-furan-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-furan-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,1aS*,8bS*)-1-{5-(5-Trifluoromethyl-isoxazol-3-yl)-furan-2-sulfonylamino}-1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-{5-(5-methyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,1aS*,8bS*)-1-{5-(5-Methyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid,-   (1R*,2S*)-2-(Acetylamino-methyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(Butyrylamino-methyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3,3-dimethyl-ureidomethyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[(cyclopropanecarbonyl-amino)-methyl]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[(cyclohexanecarbonyl-amino)-methyl]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-{[(morpholine-4-carbonyl)-amino]-methyl}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Difluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,1aS*,8bS*)-1-[5-(5-Difluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino]-1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(ethoxycarbonylamino-methyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-2-{[((S)-tetrahydro-furan-2-carbonyl)-amino]-methyl}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-methoxymethyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(1-Methyl-1H-pyrazol-4-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(4-Nitro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,1aS*,8bS*)-1-{5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino}-1,1a,2,3,4,8b-hexahydro-4-aza-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid,-   (1R*,1aS*,8bS*)-1-[4-(2,4-Dichloro-benzyloxy)-benzenesulfonylamino]-1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid hydroxyamide,-   1R*,1aS*,8bS*)-1-{5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino}-1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid hydroxyamide,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(isopropylamino-methyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-2-{[(thiazol-2-ylmethyl)-amino]-methyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-2-{[(pyridine-3-carbonyl)-amino]-methyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[(3-hydroxy-propionylamino)-methyl]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[(3-ethyl-ureido)-methyl]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(isobutyrylamino-methyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[(2-methoxy-acetylamino)-methyl]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-[(2-hydroxy-acetylamino)-methyl]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-oxo-morpholin-4-ylmethyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-[4-(5-Difluoromethyl-isoxazol-3-yl)-benzenesulfonylamino]-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-Acetylamino-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Methoxymethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-methyl-1-{5-(5-Methoxymethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2R*)-2-Carboxymethoxymethyl-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-Chloro-2-fluoro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(4-Chloro-2-fluoro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(5-Isopropyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2R*)-2-Ethoxycarbonylmethylsulfanylmethyl-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-2-Carboxymethylsulfanylmethyl-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,1aS*,4R*,8bS*)-1-{5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino}-4-hydroxy-1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid,-   (1R*,1aS*,4S*,8bS*)-1-{5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino}-4-hydroxy-1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid,-   (1S,2R)-1-{5-(3-Chloro-4-fluoro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Bromo-pyrimidin-2-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1aR*,8bS*)-5-(4-Chloro-phenyl)-thiophene-2-sulfonic acid    (2-oxo-2,3,4,8b-tetrahydro-1H-3-aza-benzo[a]cyclopropan[c]cyclohepten-1a-yl)-amide,-   (1S,2R)-1-{5-(5-Fluoro-pyridin-2-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-{5-(5-methyl-oxazol-2-yl)-thiophene-2-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-1-{5-(5-methyl-oxazol-2-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(5-Dimethylamino-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(3-Cyano-4-fluoro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-1-(5-morpholin-4-yl-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(3-Difluoromethyl-isoxazol-5-yl)-thiophene-2-sulfonylamino]-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-Dimethylamino-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(5-Ethynyl-thiophene-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(5-Acetyl-thiophene-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{4-(4-Chloro-phenyl)-piperazine-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(5-Bromo-thiophene-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-{4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(2-methoxy-ethoxymethyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,1aS*,8bS*)-1-{5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino}-4-methyl-1,1a,2,3,4,8b-hexahydro-4-aza-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid,-   (1R*,1aS*,6aS*)-1-{5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino}-1,1a,6,6a-tetrahydro-cyclopropa[a]indene-1-carboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-methylsulfanylmethyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(5-Cyclopropyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-Chloro-3-fluoro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(4-Chloro-3-fluoro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-1-[4-(4-methyl-cyclohexyl)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,1aS*,4R*,8bS*)-4-Hydroxy-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid,-   (1R*,1aS*,4S*,8bS*)-4-Hydroxy-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid,-   (1R*,1aS*,8bS*)-4-Acetyl-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-1,1a,2,3,4,8b-hexahydro-4-aza-benzo[a]cyclopropan[c]cycloheptene-1-carboxylic    acid,-   (1R*,2R*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-methanesulfonylmethyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-{4-(4-methyl-cyclohexyl)-piperazine-1-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-Isopropyl-piperazin-1-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(4-Chloro-pyrazol-1-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(8-Chloro-3,4-dihydro-1H-benzo[4,5]imidazol[1,2-a]pyrazine-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,1aS*,6aS*)-1-[4-(2,4-Dichloro-benzyloxy)-benzenesulfonylamino]-1,1a,6,6a-tetrahydro-cyclopropa[a]indene-1-carboxylic    acid,-   (1R*,1aS*,6aS*)-1-{5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino}-1,1a,6,6a-tetrahydro-cyclopropa[a]indene-1-carboxylic    acid hydroxyamide,-   (1S,2R)-1-{5-(3,5-Dichloro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(5-Benzo[1,3]dioxol-5-yl-thiophene-2-sulfonylamino)-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-{5-(1-methyl-1H-imidazol-4-yl)-thiophene-2-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-{5-(5-methyl-[1,2,4]oxadiazol-3-yl)-thiophene-2-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(3-Amino-phenyl)-thiophene-2-sulfonylamino]-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(3-Methanesulfonylamino-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{4-(4-Chloro-phenyl)-[1,4]diazepane-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4,4-Difluoro-piperidin-1-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-(5-quinoxalin-2-yl-thiophene-2-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{4-(5-Chloro-pyridin-2-yl)-piperazine-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-[4-(4-Bromo-phenyl)-piperazine-1-sulfonylamino]-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{4-(4-Chloro-3-fluoro-phenyl)-piperazine-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{4-(4-Chloro-2-fluoro-phenyl)-piperazine-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{4-(5-Chloro-pyridin-2-yl)-[1,4]diazepane-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{4-(5-Fluoro-pyridin-2-yl)-[1,4]diazepane-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(4-Benzothiazol-2-yl-piperazine-1-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,1R,3R)-1-(4-Benzoxazol-2-yl-piperazine-1-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-{4-(5-methyl-[1,3,4]thiadiazol-2-yl)-piperazine-1-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(3,5-Difluoro-pyridin-2-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(3,3-Difluoro-pyrrolidin-1-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-{5-(2-oxo-2,3-dihydro-benzothiazol-6-yl)-thiophene-2-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-{5-(2-methyl-benzothiazol-5-yl)-thiophene-2-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(5-Benzo[1,3]dioxol-5-yl-thiophene-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{4-(3-Chloro-phenyl)-[1,4]diazepane-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{4-(4-Fluoro-phenyl)-[1,4]diazepane-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(4-Benzoylamino-benzenesulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Phenyl-1-(4-phenylcarbamoyl-benzenesulfonylamino)-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-{4-(5-methyl-isoxazol-3-yl)-piperazine-1-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-{4-(5-methyl-isoxazol-3-yl)-3-oxo-piperazine-1-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-Chloro-3-nitro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-3-{5-((1S,2R)-1-Carboxy-2-methyl-2-phenyl-cyclopropylsulfamoyl)-thiophen-2-yl}-benzoic    acid ethyl ester,-   3-{5-((1S,2R)-1-Carboxy-2-methyl-2-phenyl-cyclopropylsulfamoyl)-thiophen-2-yl}-benzoic    acid,-   (1S,2R)-1-{5-(3-Acetylamino-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{6-(4-Methyl-pyrazol-1-yl)-pyridine-3-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{6-(4-Methoxy-pyrazol-1-yl)-pyridine-3-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-{4-(2-methyl-benzothiazol-5-yl)-piperazine-1-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-{4-(5-methyl-thiazol-2-yl)-piperazine-1-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1R,1aS*,7bS*)-1-{5-(5-Trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylic    acid hydroxyamide,-   (1S,2R)-1-{5-(3-Hydroxy-3H-benzotriazol-5-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-Chloro-3-dimethylamino-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Phenyl-(6-phenyl-imidazo[2,1-b]thiazole-2-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{(6-(4-Chloro-phenyl)-imidazol[2,1-b]thiazole-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{6-(4-Fluoro-phenyl)-imidazol[2,1-b]thiazole-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(4-Methoxy-pyrazol-1-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-[5-(1H-Indol-2-yl)-thiophene-2-sulfonylamino]-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(4-Bromo-pyrazol-1-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,1aS*,6aS*)-1-{5-(5-Trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-1,1a,6,6a-tetrahydro-cyclopropa[a]indene-1-carboxylic    acid hydroxyamide,-   (1S,2R,3R)-1-{5-(3-Amino-4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(5-Benzo[2,1,3]thiadiazol-5-yl-thiophene-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-Chloro-pyrazol-1-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-(6-phenyl-imidazo[2,1-b]thiazole-2-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{3-(4-Chloro-phenoxy)-pyrrolidine-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{3-(3-Chloro-phenoxy)-pyrrolidine-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{4-(4-Chloro-phenyl)-3-oxo-piperazine-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{4-(6-Chloro-pyridazin-3-yl)-piperazine-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-{3-oxo-4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(5-Bromo-1,3-dihydro-isoindole-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-2-phenyl-1-{4-(4-trifluoromethyl-pyrazol-1-yl)-benzenesulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-{4-(4-trifluoromethyl-pyrazol-1-yl)-benzenesulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*,3S*)-1-(5-Benzyl-thiophene-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*,3S*)-1-{5-(3-Hydroxy-phenyl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   4-((1S,2R)-1-Carboxy-2-phenyl-cyclopropylsulfamoyl)-piperazine-1-carboxylic    acid isopropyl ester,-   (1S,2R)-1-[4-(3-Methyl-butyl)-piperazine-1-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(4-Ethylcarbamoyl-piperazine-1-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[4-(3-Methyl-butyryl)-piperazine-1-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-{5-(3-trifluoromethyl-pyrazol-1-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-1-{5-(methyl-phenyl-amino)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-Chloro-3-methoxy-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(5-Benzo[2,1,3]oxadiazol-5-yl-thiophene-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-2-phenyl-1-(6-phenyl-imidazo[2,1-b]thiazole-2-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(6-Methoxymethyl-imidazo[2,1-b]thiazole-2-sulfonylamino)-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-[6-(4-Chloro-pyrazol-1-ylmethyl)-imidazol[2,1-b]thiazole-2-sulfonylamino]-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   1-{5-((1S,2R,3R)-1-Carboxy-2-methyl-3-phenyl-cyclopropylsulfamoyl)-thiophen-2-yl}-1H-pyrazole-4-carboxylic    acid ethyl ester,-   1-{5-((1S,2R,3R)-1-Carboxy-2-methyl-3-phenyl-cyclopropylsulfamoyl)-thiophen-2-yl}-1H-pyrazole-4-carboxylic    acid,-   (1S,2R,3R)-1-{5-[4-(1-Hydroxy-1-methyl-ethyl)-pyrazol-1-yl]-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(4-Methanesulfonyl-pyrazol-1-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*,3S*)-1-{5-(3-Hydroxymethyl-phenyl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-2-phenyl-1-(5-pyridin-4-yl-thiophene-2-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-2-phenyl-1-(5-pyridin-3-yl-thiophene-2-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(4-Benzylcarbamoyl-piperazine-1-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-{4-(3-methyl-butyl)-piperazine-1-sulfonylamino}-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-1-(4-phenethyl-piperazine-1-sulfonylamino)-3-phenyl-cyclopropanecarboxylic    acid,-   4-((1S,2R,3R)-1-Carboxy-2-methyl-3-phenyl-cyclopropylsulfamoyl)-piperazine-1-carboxylic    acid benzyl ester,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-(4-pyridin-4-yl-piperazine-1-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{4-(2-Methoxy-ethyl)-piperazine-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(3,4-Dihydro-1H-isoquinoline-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{4-(4-Methoxy-benzyl)-piperazine-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-{4-((E)-3-phenyl-allyl)-piperazine-1-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(5-Chloro-1,3-dihydro-isoindole-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2R*,3R*)-2-Methoxymethyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*,3S*)-2-Methyl-1-{5-(3-morpholin-4-ylmethyl-phenyl)-thiophene-2-sulfonylmethyl}-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*,3S*)-2-Methyl-1-(5-phenethyl-thiophene-2-sulfonylamino)-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-(5-pyrazol-1-yl-thiophene-2-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(4-Iodo-pyrazol-1-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-[4-(1-Chloro-vinyl)-pyrazol-1-yl]-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(4-Acetyl-pyrazol-1-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-[4-(1-Hydroxy-ethyl)-pyrazol-1-yl]-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(5-Hydroxy-1,3-dihydro-isoindole-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{3-(3-Chloro-benzyloxy)-pyrrolidine-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{3-(4-Chloro-benzyloxy)-pyrrolidine-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{3-(2,5-Dichloro-benzyloxy)-pyrrolidine-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(5-Isopropylamino-1,3-dihydro-isoindole-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{3-(2,4-Dichloro-benzyloxy)-pyrrolidine-1-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{6-(4-Chloro-pyrazol-1-yl)-pyridine-3-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   3-{5-((1S,2R,3R)-1-Carboxy-2-methyl-3-phenyl-cyclopropylsulfamoyl)-thiophen-2-yl}-isoxazole-5-carboxylic    acid ethyl ester,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-{6-(4-trifluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{6-(4-Chloro-pyrazol-1-yl)-pyridine-3-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Phenyl-1-{6-(4-trifluoromethyl-pyrazol-1-yl)-pyridine-3-sulfonylamino}-cyclopropanecarboxylic    acid-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-methoxy-propyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-Chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-methoxy-propyl)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(4-Hydroxymethyl-pyrazol-1-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-2-phenyl-1-{5-((E)-3,3,3-trifluoro-propenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-2-phenyl-1-{5-((Z)-3,3,3-trifluoro-propenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-Chloro-3-hydroxymethyl-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(4-Chloro-3-hydroxymethyl-phenyl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(2,4-Dichloro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(4-Cyano-phenyl)-thiophene-2-sulfonylamino]-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(7-Chloro-9H-fluorene-2-sulfonylamino)-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(7-Chloro-9H-fluorene-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(5-Imidazo[1,2-a]pyridin-2-yl-thiophene-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(5-Imidazo[1,2-a]pyrimidin-2-yl-thiophene-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-2-phenyl-1-{5-(4-trifluoromethyl-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(4-Acetyl-phenyl)-thiophene-2-sulfonylamino]-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-Hydroxymethyl-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-[3-(2-Hydroxy-ethoxy)-phenyl]-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-[3-(3-Hydroxy-propoxy)-phenyl]-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-{5-(4-trifluoromethyl-pyrazol-1-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(5-Carbamoyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(5-Cyano-isoxazol-3-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(4-Cyano-pyrazol-1-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(3,4-Difluoro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(4-Hydroxy-phenyl)-thiophene-2-sulfonylamino]-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(4-Amino-phenyl)-thiophene-2-sulfonylamino]-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(1H-Benzoimidazol-2-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-2-phenyl-1-(5-phenyl-benzo[b]thiophene-3-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-1-{5-(3-methyl-3H-[1,2,3]triazol-4-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-1-{5-(1-methyl-1H-[1,2,3]triazol-4-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Methoxy-propyl)-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(3-Fluoro-4-hydroxy-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-{5-(4-trifluromethyl-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-(5-Benzothiazol-2-yl-thiophene-2-sulfonylamino)-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(3-Hydroxymethyl-4-methoxy-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-Cyano-3-fluoro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(3-Fluoro-4-hydroxymethyl-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(3-Chloro-4-methoxy-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-(2-phenyl-3H-benzoimidazole-5-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2R*,3S*)-2,3-Dimethyl-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*,3R*)-2,3-Dimethyl-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-Methyl-2-phenyl-1-[5-(4-trifluoromethyl-pyrazol-1-yl)-thiophene-2-sulfonylamino]-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-Fluoro-3-hydroxy-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(3,4-Difluoro-5-hydroxy-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-Methanesulfonyl-pyrazol-1-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-Hydroxymethyl-pyrazol-1-yl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(5-Chloro-1H-benzoimidazol-2-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-Bromo-pyrazol-1-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-[3-(1,1-Difluoro-2-hydroxy-ethyl)-phenyl]-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-1-{5-(5-Methoxy-1H-benzoimidazol-2-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(4-Chloro-phenyl)-2-methyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Methoxy-phenyl)-2-methyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Fluoro-phenyl)-2-methyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Chloro-phenyl)-2-methyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(2-Methoxy-phenyl)-2-methyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-Methanesulfonyl-phenyl)-2-methyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(2-Fluoro-phenyl)-2-methyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(2-Chloro-phenyl)-2-methyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-Methyl-2-pyridin-3-yl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-(3-Fluoro-phenyl)-2-methyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-(3-Chloro-phenyl)-2-methyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-(4-Chloro-phenyl)-2-methyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-(4-Fluoro-phenyl)-2-methyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2-Methyl-3-phenyl-1-(2-phenyl-imidazo[1,2-a]pyridine-6-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1S,2R,3R)-2,3-Dimethyl-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-2-(3-Methoxy-phenyl)-2-methyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   and-   (1S,2R,3R)-1-{5-[5-(1,1-Difluoro-ethyl)-isoxazol-3-yl]-thiophene-2-sulfonylamino}-2,3-dimethyl-2-phenyl-cyclopropanecarboxylic    acid;    or a prodrug thereof or a pharmaceutically acceptable salt thereof;    [11] The compound of [1] above, which is represented by the formula    (1′):

whereinR¹ is selected from(1) a substituted C₁₋₆ alkyl group,and(2) —(CH₂)_(m)—X—(CH₂)_(n)-A¹,whereinm and n are the same or different and each is selected from 0 and aninteger ranging from 1 to 6,X is selected from a single bond, a C₁₋₆ alkylene group, a C₂₋₆alkenylene group, a C₂₋₆ alkynylene group, —O—, —N(R⁵)—, —S(O)_(m1)—,—CO—, —CON(R⁵)—, —N(R⁵)CO—, —SO₂N(R⁵)—, —N(R⁵)SO₂—, —N(R⁵)CON(R⁶)—,—N(R⁵) SO₂N(R⁶)—, —OCON(R⁵)— and —N(R⁵)COO—,whereinR⁵ and R⁶ are the same or different and each is selected from a hydrogenatom and a C₁₋₆ alkyl group,m1 is selected from 0 and an integer ranging from 1 to 2,A¹ is selected from a substituted C₃₋₁₄ hydrocarbon ring group and asubstituted heterocyclic group;R² and R³ are the same or different and each is selected from(1) a hydrogen atom,(2) a C₁₋₆ alkyl group,(3) a halogenated C₁₋₆ alkyl group,and(4) —(CH₂)_(p)—X₁—(CH₂)_(q)-A²¹provided that R² and R³ are not hydrogen atoms at the same time,whereinp and q are the same or different and each is selected from 0 and aninteger ranging from i to 6,X₁ is selected from a single bond, a C₁₋₆ alkylene group, a C₂₋₆alkenylene group, a C₂₋₆ alkynylene group, —O—, —N(R⁷)—, —S(O)_(m2)—,—CO—, CON(R⁷)—, —N(R⁷)CO—, —SO₂N(R⁷)—, —N(R⁷)SO₂—, N(R⁷)CON(R⁸)—,—N(R⁷)SO₂N(R⁸)—, —OCON(R⁷)— and —N(R⁷)COO—, whereinR⁷ and R⁸ are the same or different and each is selected from a hydrogenatom and a C₁₋₆alkyl group,m2 is selected from 0 and an integer ranging from 1 to 2,r is selected from 0 and an integer ranging from 1 to 2, andA² is selected from an optionally substituted C₃₋₁₄ hydrocarbon ringgroup and an optionally substituted heterocyclic group; andR⁴ is selected from

(1) —CO₂R⁹, (2) —C(O)NHOR⁹, (3) —C(O)NH—SO₂—R⁹, (4) —C(O)NHR⁹, (5) —SH,(6) —CH₂CO₂R⁹, (7) —C(O)R⁹, (8) —N(OH)COR⁹, (9) —SN₂H₂R⁹, (10) —SONHR⁹,(11) —CH₂CO₂H, (12) —PO(OH)₂, (13) —PO(OH)NHR⁹, (14) —CH₂SH and (15)—CH₂OH

whereinR⁹ is selected from a hydrogen atom, an optionally substituted C₁₀ alkylgroup and an optionally substituted C₆₋₁₄ aryl-C₁₋₆ alkyl group;or a prodrug thereof or a pharmaceutically acceptable salt thereof;[12] The compound of [11] above, wherein R¹ is —(CH₂)_(m)—X—(CH₂)_(n)-A¹and A¹ is selected from(1) an optionally substituted fused C₆₋₁₄ hydrocarbon ring group,(2) an optionally substituted fused heterocyclic group, and

(3) —V—W-Z,

whereinV is selected from an optionally substituted C₃₋₁₄ hydrocarbon ringgroup and an optionally substituted heterocyclic group;W is —(CH₂)_(t)—X₂—(CH₂)_(u)—;whereint and u are the same or different and each is selected from 0 and aninteger ranging from 1 to 6,X₂ is selected from a single bond, a C₁₋₆ alkylene group, a C₂₋₆alkenylene group, a C₂₋₆ alkynylene group, —O—, —N(R¹⁰)—, —S(O)_(m3)—,—CO—, —CON(R¹⁰)—, —N(R¹⁰)CO—, —SO₂N(R¹⁰)—, —N(R¹⁰)SO₂—,—N(R¹⁰)CON(R¹¹)—, —N(R¹⁰)SO₂N(R¹¹)—, —OCON(R¹⁰)— and —N(R¹⁰)COO—,whereinR¹⁰ and R¹¹ are the same or different and each is selected from ahydrogen atom and a C₁₋₆ alkyl group,m3 is selected from 0 and an integer ranging from 1 to 2,Z is selected from an optionally substituted C₁₋₆ alkyl group, a halogenatom, a nitro group, a cyano group, a C₁₋₆ alkoxy group, a hydroxylgroup, a halogenated C₁₋₆ alkyl group, a halogenated C₁₋₆ alkoxy group,a carboxyl group, a C₁₋₆ alkoxy-carbonyl group, an amino group, amono(C₁₋₆ alkyl)amino group, a di(C₁₋₆ alkyl)amino group, an optionallysubstituted C₃₋₁₄ hydrocarbon ring group and an optionally substitutedheterocyclic group;or a prodrug thereof or a pharmaceutically acceptable salt thereof;[13] The compound of [12] above, wherein m and n are 0, and X is asingle bond; or a prodrug thereof or a pharmaceutically acceptable saltthereof;[14] The compound of [13] above, wherein t and u are 0; or a prodrugthereof or a pharmaceutically acceptable salt thereof;[15] The compound of [14] above, wherein R⁴ is selected from —CO₂R⁹ and—C(O)NHOR⁹; or a prodrug thereof or a pharmaceutically acceptable saltthereof;[16] The compound of [15] above, wherein R⁹ is a hydrogen atom; or aprodrug thereof or a pharmaceutically acceptable salt thereof;[17] The compound of [16] above, wherein R² is—(CH₂)_(p)—X₁—(CH₂)_(q)-A²; or a prodrug thereof or a pharmaceuticallyacceptable salt thereof;[18] The compound of [11] above, which is selected from the groupconsisting of

-   (1S,2R)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[4-(2,4-dichloro-benzyloxy)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid hydroxyamide,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-{3-[(pyridin-3-ylmethyl)-amino]-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-(2-methoxy-phenyl)-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R,2R)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R,2S)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R,2R)-2-benzyl-1-(4′-chloro-biphenyl-4-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1S,2S)-2-benzyl-1-(4′-chloro-biphenyl-4-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino-2-(3-phenoxy-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-[3-(4-chloro-phenoxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4-chloro-biphenyl-4-sulfonylamino)-2-(3-methoxy-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(2-methoxy-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(2-phenoxy-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(4-methoxy-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(4-phenoxy-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(3-nitro-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-amino-phenyl)-1-(4′-chloro-biphenyl-4-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-piperidine-4-yl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(3-isobutoxy-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(3-dimethylamino-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(3-trifluoromethyl-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-bromo-phenyl)-1-(4′-chloro-biphenyl-4-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(3,5-diphenoxy-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-biphenyl-3-yl-1-(4′-chloro-biphenyl-4-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-benzyloxycarbonylamino-phenyl)-1-(4′-chloro-biphenyl-4-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4-chloro-biphenyl-4-sulfonylamino)-2-(3-isobutoxycarbonylamino-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(biphenyl-4-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4-phenoxy-benzenesulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-bromo-biphenyl-4-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-2-phenyl-1-{5-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[4-(2-methyl-2H-tetrazol-5-yl)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[4-(2-ethyl-2H-tetrazol-5-yl)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-phenyl-1-[4-(2-propyl-2H-tetrazol-5-yl)-benzenesulfonylamino]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[4-(2-isopropyl-2H-tetrazol-5-yl)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(dibenzofurane-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(3-methanesulfonylamino-phenyl)-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-pentafluoroethyl-[1,2,4]oxadiazol-3-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-acetylamino-phenyl)-1-(4′-chloro-biphenyl-4-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(3-methoxycarbonylamino-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-4-{3-{2-carboxy-2-(4′-chloro-biphenyl-4-sulfonylamino)-cyclopropyl}-phenylamino}-piperidine-1-carboxylic    acid tert-butyl ester,-   (1R*,2S*)-2-(3-benzylamino-phenyl)-1-(4′-chloro-biphenyl-4-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(3-hydroxy-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-cyclohexyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-phenyl-1-(4-thiophen-2-yl-benzenesulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-phenyl-1-(4-thiophen-3′-yl-benzenesulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[4-(4-methyl-thiophen-2-yl)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   5-[4-((1R*,2S*)-1-Carboxy-2-phenyl-cyclopropylsulfamoyl)-phenyl]-thiophene-2-carboxylic    acid,-   (1R*,2S*)-1-(9-oxo-9H-fluorene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-4-{2-carboxy-2-(4′-chloro-biphenyl-4-sulfonylamino)-cyclopropyl}-piperidine-1-carboxylic    acid tert-butyl ester,-   (1R*,2S*)-2-(3-benzenesulfonylamino-phenyl)-1-(4′-chloro-biphenyl-4-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-methoxy-biphenyl-4-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(9H-fluorene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-phenyl-1-[4-(5-phenyl-[1,2,4]oxadiazol-3-yl)-benzenesulfonylamino]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-phenyl-1-(5-phenyl-thiophene-2-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(2-hydroxy-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-phenyl-1-[4-(5-phenyl-[1,3,4]oxadiazol-2-yl)-benzenesulfonylamino]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(5-bromo-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-[3-(pyridin-2-ylamino)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-{3-[(pyridin-2-carbonyl)-amino]-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-{3-[(pyridin-4-carbonyl)-amino]-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-{3-[(pyridin-3-carbonyl)-amino]-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[4-(2,4-dichloro-benzyloxy)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-[3-(2-hydroxy-ethoxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-{3-(2-dimethylamino-acetylamino)-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-[3-(pyridin-3-yloxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-methoxy-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-{5-(4-dimethylamino-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(7-bromo-9H-fluorene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-{(3-(2-pyrrolidin-1-yl-ethoxy)-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-{3-(2-morpholin-4-yl-ethoxy)-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-{3-(2-pyrazol-1-yl-ethoxy)-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-[(3-(pyridin-3-ylmethoxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(2-isopropyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(2-benzyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-1-(4′-chloro-biphenyl-4-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(7-fluoro-9H-fluorene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S*,2S*)-1-(7-fluoro-9H-fluorene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[4-(2-ethyl-thiazol-4-yl)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-{3-(2-imidazol-1-yl-ethoxy)-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(2-benzyloxy-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(2-hydroxy-ethoxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(2-benzyloxy-phenyl)-1-{5-(4-chloro-phenylethynyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(pyridin-3-yloxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1S,2R)-2-phenyl-1-(1-phenyl-1H-pyrazole-4-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-{3-[(3H-imidazol-4-ylmethyl)-amino]-phenyl}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(7-bromo-9H-fluorene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[4-(2-methyl-thiazol-4-yl)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[4-(1-hydroxy-ethyl)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(7-chloro-9H-fluorene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[3-(6-chloro-pyridazin-3-yl)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1S*,2S*)-1-(7-chloro-9H-fluorene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[1-(4-chloro-phenyl)-1H-pyrazole-4-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-dimethylaminomethyl-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4-chloro-biphenyl-4-sulfonylamino)-2-{3-(1-methyl-piperidine-4-ylamino)-phenyl}-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[2-(4-chloro-phenyl)-thiazole-5-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-{3-{(1-methyl-1H-imidazol-2-ylmethyl)-amino}-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-(2-hydroxy-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-{[methyl-(1-methyl-piperidine-4-yl)-amino]-methyl}-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-[3-(2-hydroxy-acetylamino)-phenyl]-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(4-chloro-phenyl)-4-methyl-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(pyridin-3-ylmethoxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(pyridin-2-ylmethoxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1R,2S)-1-(7-bromo-9H-fluorene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(3-chloro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-[3-(pyridine-3-sulfonylamino)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-{3-[(1H-imidazol-2-ylmethyl)-amino]-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-3-{2-carboxy-2-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-cyclopropyl}-benzoic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(3-dimethylcarbamoylmethoxy-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-methoxy-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-hydroxy-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-carbamoylmethoxy-phenyl)-(4′-chloro-biphenyl-4-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(4′-chloro-biphenyl-4-sulfonylamino)-2-(3-methylcarbamoylmethoxy-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-carboxymethoxy-phenyl)-1-(4′-chloro-biphenyl-4-sulfonylamino)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(5-isooxazol-3-yl-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-phenyl-1-{5-(5-trifluoromethyl-isooxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1S*,2R*)-1-(7-chloro-dibenzofurane-3-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S*,2S*)-1-(7-chloro-dibenzofurane-3-sulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(2-chloro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-[5-(2,4-dichloro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1S,2R)-1-(2-benzofuran-2-yl-ethansulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-nitro-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-amino-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-{3-[(pyridin-3-ylmethyl)-amino]-phenyl}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-methanesulfonylamino-phenyl)-cyclopropanecarboxylic    acid,-   (1S,2R)-1-{5-(5-chloro-pyridin-2-yl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-trifluoromethanesulfonylamino-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-dimethylamino-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-hydroxymethyl-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-(3-ureido-phenyl)-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(pyridine-3-sulfonylamino)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(3-carbamoyl-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-[2-(2-hydroxy-ethoxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-(2-carboxymethoxy-phenyl)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-(3-phenoxy-benzenesulfonylamino)-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[3-(4-fluoro-phenoxy)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[3-(4-chloro-phenoxy)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[3-(3,4-dichloro-phenoxy)-benzenesulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[4-(4-chloro-phenyl)-piperazin-1-sulfonylamino]-2-phenyl-cyclopropanecarboxylic    acid,-   (1R*,2S*)-2-[2-(benzylcarbamoyl-methoxy)-phenyl]-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-[2-(2-morpholin-4-yl-2-oxo-ethoxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-[2-(isopropylcarbamoyl-methoxy)-phenyl]-cyclopropanecarboxylic    acid,-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-[3-(pyridin-3-ylaminomethyl)-phenyl]-cyclopropanecarboxylic    acid,-   and-   (1R*,2S*)-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-methyl-2-phenyl-cyclopropanecarboxylic    acid;    or a prodrug thereof or a pharmaceutically acceptable salt thereof;    [19] A pharmaceutical composition comprising a compound of any of    [1] to [18] above, a prodrug thereof or a pharmaceutically    acceptable salt thereof, and a pharmaceutically acceptable carrier;    [20] An aggrecanase inhibitor comprising a compound of any of [1] to    [18] above, or a prodrug thereof or a pharmaceutically acceptable    salt thereof as an active ingredient;    [21] An MMP inhibitor comprising a compound of any of [1] to [18]    above, or a prodrug thereof or a pharmaceutically acceptable salt    thereof as an active ingredient;    [22] The MMP inhibitor of [21] above, which is an MMP-13 inhibitor;    [23] A prophylactic or therapeutic agent for osteoarthritis    comprising a compound of any of [1] to [18] above, a prodrug thereof    or a pharmaceutically acceptable salt thereof as an active    ingredient;    [24] A prophylactic or therapeutic agent for rheumatoid arthritis    comprising a compound of any of [1] to [18] above, a prodrug thereof    or a pharmaceutically acceptable salt thereof as an active    ingredient;    [25] A method for preventing or treating osteoarthritis, which    comprises administering a compound of any of [1] to [18] above, a    prodrug thereof or a pharmaceutically acceptable salt thereof to a    mammal;    [26] A method for preventing or treating rheumatoid arthritis, which    comprises administering a compound of any of [1] to [18] above, a    prodrug thereof or a pharmaceutically acceptable salt thereof to a    mammal;    [27] The agent of [23] above, which is used in combination with a    different therapeutic agent for osteoarthritis;    [28] The agent of [23] above, which is used in combination with a    different therapeutic agent for rheumatoid arthritis;    [29] The agent of [24] above, which is used in combination with a    different therapeutic agent for osteoarthritis;    [30] The agent of [24] above, which is used in combination with a    different therapeutic agent for rheumatoid arthritis;    [31] The method of [25] above, which is used in combination with a    different therapeutic agent for osteoarthritis;    [32] The method of [25] above, which is used in combination with a    different therapeutic agent for rheumatoid arthritis;    [33] The method of [26] above, which is used in combination with a    different therapeutic agent for osteoarthritis;    [34] The method of [26] above, which is used in combination with a    different therapeutic agent for rheumatoid arthritis.

DETAILED DESCRIPTION OF THE INVENTION

The definitions of respective substituents and moieties used in thepresent specification are as follows.

In the present specification, “C₁₋₆” means that the number of carbonatoms ranges from 1 to 6.

The “single bond” means a direct connection. In—(CH₂)_(m)—X—(CH₂)_(n)-A¹, for example, when X is a “single bond”, it is—(CH₂)_(m)—(CH₂)_(n)-A¹.

The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atomor an iodine atom, preferably a fluorine atom, a chlorine atom or abromine atom.

The “C₁₋₁₀ alkyl group” is a straight chain or branched chain alkylgroup having 1 to 10 carbon atoms, and is exemplified by methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neo-pentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl,heptyl, octyl, nonyl, decyl and the like. In some embodiments of thepresent invention, it is a straight chain or branched chain alkyl grouphaving 1 to 6 carbon atoms.

The “C₁₋₆ alkyl group” is a straight chain or branched chain alkyl grouphaving 1 to 6 carbon atoms, and is exemplified by methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,tert-pentyl, hexyl and the like. In some embodiments of the presentinvention, it is a straight chain or branched chain alkyl group having 1to 4 carbon atoms.

The “C₂₋₆ alkenyl group” is a straight chain or branched chain alkenylgroup having 2 to 6 carbon atoms, and is exemplified by ethenyl (vinyl),1-propenyl, 2-propenyl (allyl), isopropenyl, 1-butenyl, 2-butenyl,3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl,2-methyl-2-propenyl, 1-ethylvinyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl,1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-methyl-1-butenyl,1-methyl-2-butenyl, 2-methyl-1-butenyl, 1-isopropylvinyl,2,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,2,4-hexadienyl, 1-methyl-1-pentenyl and the like. In some embodiments ofthe present invention, it is a straight chain or branched chain alkenylgroup having 2 to 4 carbon atoms.

The “C₂₋₆ alkynyl group” is a straight chain or branched chain alkynylgroup having-2 to 6 carbon atoms, and is exemplified by ethynyl,propynyl, butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and thelike.

The “C₁₋₆ alkoxy group” is an alkyloxy group wherein the alkyl moietythereof is the above-defined C₁₋₆ alkyl group. Examples thereof includemethoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy,tert-butyloxy, pentyloxy, hexyloxy and the like. In some embodiments ofthe present invention, it is an alkoxy group wherein the alkyl moietythereof is a straight chain or branched chain alkyl group having 1 to 4carbon atoms.

The “halogenated C₁₋₆ alkyl group” is the above-defined C₁₋₆ alkyl groupexcept that it is substituted by the above-defined halogen atom.Examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl,bromomethyl, chloromethyl, 1,2-dichloromethyl, 2,2-dichloromethyl,2,2,2-trifluoroethyl and the like. In some embodiments of the presentinvention, it is a halogenated alkyl group wherein the alkyl moietythereof is a straight chain or branched chain alkyl group having 1 to 4carbon atoms.

The “halogenated C₁₋₆ alkoxy group” is the above-defined C₁₋₆ alkoxygroup except that it is substituted by the above-defined halogen atom.Examples thereof include fluoromethoxy, difluoromethoxy,trifluoromethoxy, bromomethoxy, chloromethoxy, 1,2-dichloromethoxy,2,2-dichloromethoxy, 2,2,2-trifluoroethoxy and the like. In someembodiments of the present invention, it is a halogenated alkoxy groupwherein the alkoxy moiety thereof is a straight chain or branched chainalkoxy group having 1 to 4 carbon atoms.

The “mono(C₁₋₆ alkyl)amino group” is a mono-alkylamino group wherein thealkyl moiety thereof is the above-defined C₁₋₆ alkyl group. Examplesthereof include methylamino, ethylamino, propylamino, isopropylamino,butylamino, isobutylamino, tert-butylamino, pentylamino, hexylamino andthe like. In some embodiments of the present invention, it is amono-alkylamino group wherein the alkyl moiety thereof is a straightchain or branched chain alkyl group having 1 to 4 carbon atoms.

The “di(C₁₋₆ alkyl)amino group” is a di-alkylamino group wherein thealkyl moiety thereof is the above-defined C₁₋₆ alkyl group. Examplesthereof include dimethylamino, diethylamino, dipropylamino and the like.In some embodiments of the present invention, it is a di-alkylaminogroup wherein the alkyl moiety thereof is a straight chain or branchedchain alkyl group having 1 to 4 carbon atoms.

The “C₁₋₆ alkoxy-carbonyl group” is an alkyloxycarbonyl group whereinthe alkoxy moiety thereof is the above-defined C₁₋₆ alkoxy group.Examples thereof include methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropyloxycarbonyl, butoxycarbonyl,isobutyloxycarbonyl, tert-butyloxycarbonyl, pentyloxycarbonyl,hexyloxycarbonyl and the like. In some embodiments of the presentinvention, it is an alkoxycarbonyl group wherein the alkyl moietythereof is a straight chain or branched chain alkyl group having 1 to 4carbon atoms.

The “C₁₋₆ alkoxy-C₁₋₆ alkyl group” is an alkoxy-alkyl group wherein thealkoxy moiety thereof is the above-defined C₁₋₆ alkoxy group and thealkyl moiety thereof is the above-defined C₁₋₆ alkyl group. Examplesthereof include methoxymethyl, ethoxymethyl, propoxymethyl,butoxymethyl, pentyloxymethyl, hexyloxymethyl, methoxyethyl,ethoxyethyl, propoxyethyl, butoxyethyl, pentyloxyethyl, hexyloxyethyland the like. In some embodiments of the present invention, it is a C₁₋₄alkoxy-C₁₋₄ alkyl group wherein the alkoxy moiety thereof is a straightchain or branched chain alkoxy group having 1 to 4 carbon atoms and thealkyl moiety thereof is a straight chain or branched chain alkyl grouphaving 1 to 4 carbon atoms.

The “C₁₋₆ alkyl-aminocarbonyl group” is a mono-alkyl-amino-carbonylgroup wherein the alkyl moiety thereof is the above-defined C₁₋₆ alkylgroup. Examples thereof include methylaminocarbonyl, ethylaminocarbonyl,propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl,isobutylaminocarbonyl, tert-butylaminocarbonyl, pentylaminocarbonyl,hexylaminocarbonyl and the like. In some embodiments of the presentinvention, it is a C₁₋₄ alkyl-aminocarbonyl group wherein the alkylmoiety thereof is a straight chain or branched chain alkyl group having1 to 4 carbon atoms.

The “C₁₋₆ alkyl-carbonylamino group” is a mono-alkylcarbonyl-amino groupwherein the alkyl moiety thereof is the above-defined C₁₋₆ alkyl group.Examples thereof include methylcarbonylamino, ethylcarbonylamino,propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino,isobutylcarbonylamino, tert-butylcarbonylamino, pentylcarbonylamino,hexylcarbonylamino and the like. In some embodiments of the presentinvention, it is a mono-alkylcarbonyl-amino group wherein the alkylmoiety thereof is a straight chain or branched chain alkyl group having1 to 4 carbon atoms.

The “C₁₋₆ alkylsulfonyl group” is an alkylsulfonyl group wherein thealkyl moiety thereof is the above-defined C₁₋₆ alkyl group. Examplesthereof include methanesulfonyl, ethanesulfonyl, propanesulfonyl,butanesulfonyl, penanesulfonyl, hexanesulfonyl and the like. In someembodiments of the present invention, it is an alkylsulfonyl groupwherein the alkyl moiety thereof is a straight chain or branched chainalkyl group having 1 to 4 carbon atoms.

The “C₁₋₆ alkylsulfonylamino group” is an alkylsulfonyl-amino groupwherein the alkyl moiety thereof is the above-defined C₁₋₆ alkyl group.Examples thereof include methanesulfonylamino, ethanesulfonylamino,propanesulfonylamino, butanesulfonylamino, pentanesulfonylamino,hexanesulfonylamino and the like. In some embodiments of the presentinvention, it is an alkylsulfonylamino group wherein the alkyl moietythereof is a straight chain or branched chain alkyl group having 1 to 4carbon atoms.

The “C₁₋₆ alkylene group” is a straight chain or branched chain alkylenegroup having 1 to 6 carbon atoms, and is exemplified by methylene,ethylene, trimethylene, tetramethylene, pentamethylene, hexamethyleneand the like.

The “C₂₋₆ alkenylene group” is a straight chain or branched chainalkenylene group having 2 to 6 carbon atoms, and is exemplified byvinylene, propenylene, 1-butenylene, 1,3-butadienylene and the like.

The “C₂₋₆ alkynylene group” is a straight chain or branched chainalkynylene group having 2 to 6 carbon atoms, such as a straight chain orbranched chain alkynylene group having 2 to 4 carbon atoms, for exampleethynylene.

The “C₂₋₆ acyl group” is an alkanoyl group having 2 to 6 carbon atoms,and is exemplified by, acetyl, propionyl, butyryl, pivaloyl and thelike. In some embodiments of the present invention, it is acetyl,pivaloyl and the like.

The “substituted C₁₋₆ alkyl group” is the above-defined C₁₋₆ alkyl groupexcept that it is substituted by 1 to 5, for example 1 to 3,substituent(s). The substituent of the substituted C₁₋₆ alkyl groupinclude

(i) a halogen atom,(ii) a nitro group,(iii) a cyano group,(iv) a C₁₋₆ alkoxy group,(v) a hydroxyl group,(vi) a halogenated C₁₋₆ alkoxy group,(vii) a carboxyl group,(viii) a C₁₋₆ alkoxy-carbonyl group,(ix) an amino group,(x) a mono(C₁₋₆ alkyl)amino group,(xi) a di(C₁₋₆ alkyl)amino group,(xii) an optionally substituted C₃₋₁₄ hydrocarbon ring group,(xiii) an optionally substituted heterocyclic group,(xiv) —W-Z (as defined above),(xv) —W¹-Z¹ (defined below),(xvi) a group selected from the above-mentioned group B,(xvii) a group selected from the above-mentioned group C, and the like.

The “optionally substituted C₁₋₆ alkyl group” includes the above-definedsubstituted C₁₋₆ alkyl group and an unsubstituted C₁₋₆ alkyl group.

The “optionally substituted C₁₋₁₀ alkyl group” is that wherein theabove-defined C₁₋₁₀ alkyl group is optionally substituted by 1 to 5, forexample 1 to 3, substituent(s) and includes an unsubstituted C₁₋₁₀ alkylgroup. Substituents of the optionally substituted C₁₋₁₀ alkyl groupinclude substituents similar to those mentioned above for a substitutedC₁₋₆ alkyl group. In some embodiments, it is a straight chain orbranched chain alkyl group having 1 to 6 carbon atoms, which issubstituted or unsubstituted by the above-mentioned substituents.

The “C₃₋₁₄ hydrocarbon ring group” is a saturated or unsaturated cyclichydrocarbon group having 3 to 14 carbon atoms and includes a C₆₋₁₄ arylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₈ cycloalkenyl group and the like.

The “C₆₋₁₄ aryl group” is an aromatic hydrocarbon group having 6 to 14carbon atoms. Examples thereof include phenyl, naphthyl, azulenyl,anthryl, phenanthryl and the like, for example, some embodiments includephenyl.

The “C₃₋₁₀ cycloalkyl group” is a saturated cycloalkyl group having 3 to10 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, norbornanyland the like, for example, some embodiments include cyclopentyl,cyclohexyl or cycloheptyl.

The “C₃₋₈ cycloalkenyl group” is a cycloalkenyl group having at least 1,preferably 1 or 2, double bond(s) and 3 to 8 carbon atoms. Examplesthereof include cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclopentadienyl, cyclohexenyl (e.g., 2,4-cyclohexadien-1-yl,2,5-cyclohexadien-1-yl, etc.), cycloheptenyl, cyclooctenyl and the like.

The “substituted C₃₋₁₄ hydrocarbon ring group” is the above-definedC₃₋₁₄ hydrocarbon ring group except that it is substituted by 1 to 5,for example 1 to 3, substituent(s). The substituent of the substitutedC₃₋₁₄ hydrocarbon ring group include

(i) an optionally substituted C₁₋₆ alkyl group,(ii) a halogen atom,(iii) a nitro group,(iv) a cyano group,(v) a C₁₋₆ alkoxy group,(vi) a hydroxyl group,(vii) a halogenated C₁₋₆ alkyl group,(viii) a halogenated C₁₋₆ alkoxy group,(ix) a carboxyl group,(x) a C₁₋₆ alkoxy-carbonyl group,(xi) an amino group,(xii) a mono(C₁₋₆ alkyl)amino group,(xiii) a di(C₁₋₆alkyl)amino group,(xiv) an optionally substituted C₃₋₁₄ hydrocarbon ring group,(xv) an optionally substituted heterocyclic group,(xvi) —W-Z (as defined above),(xvii) —W¹-Z¹ (defined below),(xviii) a group represented by the formula —(CH₂)_(m4)—X₄—(CH₂)_(n4)—R²⁴wherein each symbol is as defined above,(xix) a group represented by the formula

wherein each symbol is as defined above,(xx) a group selected from the above-mentioned group B,(xxi) a group selected from the above-mentioned group C, and the like.

The “substituted C₃₋₁₄ hydrocarbon ring group” may take together withthe substituent(s) to form an “optionally substituted fused C₆₋₁₄hydrocarbon ring group” or an “optionally substituted fused heterocyclicgroup”.

The “fused C₆₋₁₄ hydrocarbon ring group” in the “optionally substitutedfused C₆₋₁₄ hydrocarbon ring group” includes, for example, a saturatedor unsaturated (including partially unsaturated and completelyunsaturated) fused hydrocarbon ring group having 6 to 14 carbon atoms,wherein C₃₋₁₄ hydrocarbon ring groups defined above have been fused.Examples thereof include indenyl, indanyl, 1,4-dihydronaphthyl,fluorenyl, 9-oxo-fluorenyl, 1,2,3,4-tetrahydronaphthyl(1,2,3,4-tetrahydro-2-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl and thelike), perhydronaphthyl and the like. For example, it is a fused ringgroup of phenyl and a different ring group, and fluorenyl,9-oxo-fluorenyl and the like.

Examples of substituent of the “optionally substituted fused C₆₋₁₄hydrocarbon ring group” include substituents similar to those mentionedabove for the “substituted C₃₋₁₄ hydrocarbon ring group”.

The “optionally substituted C₃₋₁₄ hydrocarbon ring group” includes the“substituted C₃₋₁₄ hydrocarbon ring group” and an unsubstituted C₃₋₁₄hydrocarbon ring group.

The “heterocyclic group” is a 5-membered or 6-membered saturated orunsaturated (including partially unsaturated and completely unsaturated)monocyclic heterocyclic group having, as an atom constituting the ring,at least 1, for example 1 to 4, heteroatoms selected from an oxygenatom, a nitrogen atom and a sulfur atom, besides a carbon atom.

The “saturated monocyclic heterocyclic group” include, for example,pyrrolidinyl, 2-oxo-pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl,imidazolidinyl, 2-oxo-imidazolidinyl, 2,4-dioxo-imidazolidinyl,pyrazolydinyl, 1,3-dioxolanyl, 1,3-oxathiolanyl, oxazolidinyl,2-oxo-oxazolidinyl, thiazolidinyl, 2-oxo-thiazolidinyl,2,4-dioxo-thiazolidinyl, 4-oxo-2-thioxo-thiazolidinyl, piperidinyl,2-oxopiperidinyl, piperazinyl, 2,5-dioxopiperazinyl,hexahydropyridazinyl, 3-oxotetrahydropyridazinyl,2-oxotetrahydropyrimidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,dioxanyl, morpholinyl, 3-oxomorpholinyl, thiomorpholinyl,3-oxothiomorpholinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl,4-oxopiperidinyl, 2,6-dioxopiperidinyl, 2-oxo-1,3-oxazinanyl,2-oxo-1,3-thiazinanyl, azetidinyl, 1,4-diazepanyl,

and the like, preferably, pyrrolidinyl, piperidinyl and morpholinyl.

The “unsaturated monocyclic heterocyclic group” includes, for example,pyrrolyl, 1,5-dihydro-2-oxopyrrolyl, furyl, thienyl, imidazolyl,1,2-dihydro-2-oxoimidazolyl, 1,3-dihydro-2-oxoimidazolyl, pyrazolyl,1,2-dihydro-3-oxopyrazolyl, oxazolyl, 2-oxo-oxazolyl, isoxazolyl,thiazolyl, 2-oxothiazolyl, isothiazolyl, 1,2,4-triazolyl,3-oxo-1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, 1,3,4-oxadiazolyl,1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 1,3,4-thiadiazinyl,1,3,4-thiadiazolyl, 2-thioxo-1,3,4-thiadiazolyl, 3-oxo-1,4-oxazinyl,1,2,4-thiadiazolyl, 5-oxo-1,2,4-thiadiazolyl, furazanyl, pyridyl,2-oxopyridyl, 4-oxopyridyl, 2-thioxopyridyl, 4-thioxopyridyl,pyrimidinyl, 2-oxopyrimidinyl, 3,4-dihydro-4-oxopyrimidinyl,2,4,6-trioxopyrimidinyl, pyridazinyl, 3-oxopyridazinyl, pyrazinyl,1,3,5-triazinyl, imidazolinyl, pyrazolinyl, oxazolinyl (2-oxazolinyl,3-oxazolinyl, 4-oxazolinyl), isoxazolinyl, thiazolinyl, isothiazolinyl,pyranyl, 2-oxopyranyl, 4-oxopyranyl, 4-thioxopyranyl and the like, suchas, imidazolyl, pyrazolyl, isoxazolyl, thiazolyl, 1,2,4-triazolyl,tetrazolyl., 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl and oxazolinyl.

The “substituted heterocyclic group” is the above-defined heterocyclicgroup except that it is substituted by 1 to 5, for example 1 to 3,substituent(s). As the substituent thereof, examples includesubstituents similar to those mentioned above for “substituted C₃₋₁₄hydrocarbon ring group”.

The “substituted heterocyclic group” may take together with thesubstituent(s) thereof to form an “optionally substituted fusedheterocyclic group”.

The “fused heterocyclic group” in the “optionally substituted fusedheterocyclic group” includes, for example, a 6-membered to 14-memberedsaturated or unsaturated (including partially unsaturated and completelyunsaturated) fused heterocyclic group having, as an atom constitutingthe ring, at least 1, for example 1 to 4, heteroatoms selected from anoxygen atom, a nitrogen atom and a sulfur atom, besides a carbon atom.The fused heterocyclic group may be a fused ring group of a saturated orunsaturated heterocyclic group defined above and a C₃₋₁₄ hydrocarbonring group defined above, or may be a fused ring group of saturated orunsaturated heterocyclic groups defined above. Examples thereof includeindolyl, isoindolyl, 2,3-dihydroindolyl, 2,3-dihydroisoindolyl,1,3-dihydro-2-oxoisoindolyl, 2,3-dihydro-1-oxoisoindolyl,1,3-dihydro-1,3-dioxoisoindolyl, benzimidazolyl, indazolyl,4,5,6,7-tetrahydroindazolyl, benzotriazolyl, benzothiazolyl,benzoisothiazolyl, 4,5,6,7-tetrahydrobenzoisothiazolyl,2-oxobenzothiazolyl, benzothiophenyl, dibenzothiophenyl,4,5,6,7-tetrahydrobenzothiophenyl, benzofuranyl, dibenzofuranyl,isobenzofuranyl, 4,5,6,7-tetrahydrobenzofuranyl,4,5,6,7-tetrahydroisobenzofuranyl, benzoxazolyl, benzoisooxazolyl,2-oxobenzoxazolyl, 4,5,6,7-tetrahydroisobenzoxazolyl, indolizinyl,quinolyl, isoquinolyl, 1,2-dihydro-2-oxoquinolyl, quinazolinyl,quinoxalinyl, cinnolinyl, phthalazinyl, quinolidinyl, carbazolyl, puryl,pteridinyl, indolinyl, isoindolinyl, 4,5,6,7-tetrahydroindolyl,4,5,6,7-tetrahydroisoindolyl, 5,6,7,8-tetrahydroquinolyl,1,2,3,4-tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl,1,2,3,4-tetrahydroisoquinolyl, 2-oxo-1,2,3,4-tetrahydroisoquinolyl,1,3-benzodioxolyl, 3,4-methylenedioxypyridyl,4,5-ethylenedioxypyrimidinyl, chromenyl, chromanyl, isochromanyl,1,2,4-benzotriazinyl, 6,7-dihydropyrindinyl,6,7-dihydrocyclopentapyrazinyl, 6,7-dihydrocyclopentapyridazinyl,6,7-dihydrocyclopentapyrimidinyl, 2,3,4,5-tetrahydrobenzoazepinyl,

and the like, for example, some embodiments include benzofuran yl,dibenzofuranyl, or isoquinolyl.

Examples of substituents of the “optionally substituted fusedheterocyclic group” include substituents similar to those mentionedabove for “substituted heterocyclic group”.

The “optionally substituted heterocyclic group” includes theabove-defined “substituted heterocyclic group” and the unsubstitutedheterocyclic group.

The “C₆₋₁₄ aryl-C₁₋₆ alkyl group” is an arylalkyl group wherein thealkyl moiety thereof is the above-defined C₁₋₆ alkyl group and the arylmoiety is the above-defined C₆₋₁₄ aryl group. Examples thereof includebenzyl, phenethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl and thelike. In some embodiments of the present invention, it is an arylalkylgroup wherein the alkyl moiety thereof is a straight chain alkyl grouphaving 1 to 4 carbon atoms and the aryl moiety is phenyl.

The “optionally substituted C₆₋₁₄ aryl-C₁₋₆ alkyl group” is that whereinthe above-defined C₆₋₁₄ aryl-C₁₋₆ alkyl group is optionally substitutedby 1 to 5, preferably 1 to 3, substituent(s) and includes anunsubstituted C₆₋₁₄ aryl-C₁₋₆ alkyl group. Substituents of theoptionally substituted C₆₋₁₄ aryl-C₁₋₆ alkyl group include substituentssimilar to those mentioned above for the substituted C₃₋₁₄ hydrocarbonring group. In some embodiments of the present invention, it is aphenyl-C₁₋₁₄ alkyl group substituted or unsubstituted by theabove-mentioned substituents.

Each symbol in the formula (1) of preferable compounds of the formula(1) is explained in the following.

In some embodiments of the inventive compounds of formula (1), R¹ is forexample —(CH₂)_(m)—X—(CH₂)_(n)-A¹ wherein each symbol is as definedabove.

m and n are the same or different and each is for example 0 or aninteger ranging from 1 to 2, preferably 0.

X is for example a single bond or a C₂₋₆ alkenylene group (e.g.,vinylene), preferably a single bond.

A¹ is for example a group of the following formula

wherein each symbol is as defined above.

The C₃₋₁₄ hydrocarbon ring group at ring A¹⁰ is for example a C₆₋₁₄ arylgroup, preferably phenyl.

The heterocyclic group at ring A¹⁰ is for example a saturated monocyclicheterocyclic group (e.g., azetidinyl, pyrrolidinyl, piperazinyl,piperazinonyl, piperidinyl, 1,4-diazepanyl, 3-oxo-piperazinyl) or anunsaturated monocyclic heterocyclic group (e.g., thienyl, methylthienyl,pyrazolyl, thiazolyl, pyridyl, 1,2,3,6-tetrahydropyridyl), preferablythienyl, azetidinyl, pyrrolidinyl, piperazinyl, piperazinonyl,piperidinyl, thienyl, pyridyl, 1,2,3,6-tetrahydropyridyl or3-oxo-piperazinyl.

r is for example 0 or an integer ranging from 2 to 4.

R²² is —(CH₂)_(m4)—X₄—(CH₂)_(n4)—R²⁴ wherein each symbol is as definedabove.

m4 and n4 is for example 0 or an integer ranging from 1 to 2, preferably0.

X₄ is for example a single bond, —O—, —CO—, a C₂₋₆ alkynylene group(e.g., ethynylene) or —CON(R⁵)— (preferably R⁵ is hydrogen atom),preferably a single bond.

R²⁴ is for example a halogen atom (e.g., a chlorine atom, a bromineatom, a fluorine atom), a halogenated C₁₋₆ alkyl group (e.g.,trifluoromethyl) or a C₁₋₆ alkyl group optionally substituted byhydroxyl groups (e.g., methyl, ethyl, propyl, isopropyl, t-butyl,1-hydroxyethyl, 1-hydroxy-1-methylethyl).

The substituents R²² are the same or different when r is an integerselected from the range of 2 to 4,

R²³ is

wherein each symbol is as defined above.

m5 and n5 are the same or different and each is for example 0 or aninteger ranging from 1 to 2, preferably 0.

X₅ is for example a single bond, —O—, —CO—, —S(O)_(m1)— (preferably m1is 2) or —CON(R⁵)— (preferably R⁵ is a hydrogen atom), preferably asingle bond.

The C₃₋₁₄ hydrocarbon ring group at ring A¹¹ is for example a C₃₋₁₀cycloalkyl group (e.g., cyclopropyl, cyclopentyl) or a C₆₋₁₄ aryl group(e.g., phenyl), preferably cyclopropyl, cyclopentyl and phenyl.

The heterocyclic group at ring A¹¹ is for example a saturated monocyclicheterocyclic group (e.g., pyrrolidinyl, 2-oxo-pyrrolidinyl,2-oxo-piperidinyl, morpholinyl, piperazinyl, piperidinyl) or anunsaturated monocyclic heterocyclic group (e.g., pyrazolyl, imidazolyl,thiazolyl, pyridyl, 3,6-dihydro-2H-pyridyl, 1,2,3,6-tetrahydro-pyridyl,pyridazinyl, pyrimidinyl, 1,2,3-triazolyl, thienyl, oxazolyl,4,5-dihydro-oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, tetrazolyl,isooxazolyl, 4,5-dihydroisooxazolyl, isothiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl).

The ring A¹¹ is optionally substituted by 1 to 5 groups of the formula“—(CH₂)_(m6)—X₆—(CH₂)_(n6)—R²⁵”, which are the same or different. Thenumber of substituents is for example 1 or 2.

m6 and n6 are the same or different and each is for example 0 or aninteger ranging from 1 to 2, preferably 0.

X₆ is for example a single bond, —O—, —CO— or —COO—, preferably a singlebond.

R²⁵ is for example.

(a) a halogen atom (e.g., a chlorine atom, a bromine atom, a fluorineatom),(b) a hydroxyl group,(c) a cyano group,(d) a carboxyl group,(e) an amino group,(f) a halogenated C₁₋₆-alkyl group (e.g., fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl),(g) a C₁₋₆ alkyl group optionally substituted by hydroxyl groups (e.g.,methyl, ethyl, propyl, isopropyl, t-butyl),(h) a C₁₋₆ alkoxy group optionally substituted by hydroxyl groups,(e.g., methoxy),(i) a di(C₁₋₆ alkyl)amino group (e.g., dimethylamino)or(j) a C₃₋₁₄ hydrocarbon ring group optionally substituted by 1 to 5substituent(s) selected from the above-mentioned group B (e.g., a C₆₋₁₄aryl group, preferably phenyl).

The ring A¹¹ is may take together with a group of the formula“—(CH₂)_(m6)—X₆—(CH₂)_(n6)—R²⁵” to form an optionally substituted fusedring group. The optionally substituted fused ring group is for examplethe above-defined “optionally substituted fused C₆₋₁₄ hydrocarbon ringgroup”, the above-defined “optionally substituted fused heterocyclicgroup” or the like.

The “fused C₆₋₁₄ hydrocarbon ring group” in the “optionally substitutedfused C₆₋₁₄ hydrocarbon ring group” is for example 9H-fluorenyl or9-oxo-9H-fluorenyl, preferably 9H-fluorenyl. The substituent thereof isfor example a halogen atom (e.g., a chlorine atom, a bromine atom, afluorine atom). The number of substituents is for example 1. Examplesthereof include 9H-fluoren-2-yl, 9-oxo-9H-fluoren-2-yl,7-bromo-9H-fluoren-2-yl, 7-fluoro-9H-fluoren-2-yl,7-chloro-9H-fluoren-2-yl and the like.

The “fused heterocyclic group” in the “optionally substituted fusedheterocyclic group” is for example benzothienyl, benzothiazolyl,benzooxazolyl, benzofuranyl, benzoimidazolyl, indolyl, 5-indolizinyl,4,5,6,7-tetrahydrobenzo[d]isooxazolyl, 1,3-benzodioxolyl,5-quinoxalinyl, 2-oxo-2,3-dihydro-benzothiazolyl, 1,4-benzodioxanyl,3H-benzotriazolyl, benzo[2,1,3]thiadiazolyl, benzo[2,1,3]oxadiazolyl,benzo[1,3]dioxazolyl, imidazo[1,2-a]pyrimidinyl or the like. Thesubstituent thereof is for example a hydroxyl group, a halogen atom(e.g., a chlorine atom, a fluorine atom), a C₁₋₆ alkyl group (e.g.,methyl), a C₁₋₆ alkoxy group (e.g., methoxy) or the like. The number ofsubstituents is for example 1 or 2.

The ring A¹⁰ and the ring All may be taken together with a substituentthereof to form an optionally substituted fused ring group. Theoptionally substituted fused ring group is for example the above-defined“optionally substituted fused C₆₋₁₄ hydrocarbon ring group”, theabove-defined “optionally substituted fused heterocyclic group” or thelike.

The “fused C₆₋₁₄ hydrocarbon ring group” in the “optionally substitutedfused C₆₋₁₄ hydrocarbon ring group” is for example 9H-fluorenyl or9-oxo-9H-fluorenyl, preferably 9H-fluorenyl. The substituent thereof isfor example a halogen atom (e.g., a chlorine atom, a bromine atom, afluorine atom) or the like. The number of substituents is for example 1.Examples thereof include 9H-fluoren-2-yl, 9-oxo-9H-fluoren-2-yl,7-bromo-9H-fluoren-2-yl, 7-fluoro-9H-fluoren-2-yl,7-chloro-9H-fluoren-2-yl and the like.

The “fused heterocyclic group” in the “optionally substituted fusedheterocyclic group” is for example benzofuranyl, dibenzofuranyl,1,3,4,9-tetrahydro-p-carbolinyl,5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazinyl,7,8-dihydro-5H-pyrido[4,3-d]pyrimidinyl,3,4-dihydro-1H-pyrazino[1,2-a]indolyl, 2,3-dihydro-1H-isoindolyl,3,4-dihydro-1H-benzo[4,5]imidazo[1,2-a]pyrazinyl,imidazo[2,1-b]thiazolyl, 1,3-dihydroisoindolyl, imidazothiazolyl,3,4-dihydroisoquinolyl, dihydroisoindolyl, benzo[b]thienyl,benzoimidazolyl, imidazo[1,2-a]pyridyl or the like. The substituentthereof is for example a hydroxyl group, a halogen atom (e.g., achlorine atom, a bromine atom, a fluorine atom), a C₁₋₆ alkoxy group(e.g., methoxy), an optionally substituted C₃₋₁₄ hydrocarbon ring group(e.g., an optionally substituted C₃₋₁₀ cycloalkyl group (e.g.,cyclohexyl), an optionally substituted C₆₋₁₄ aryl group (e.g., phenyl,chlorophenyl, fluorophenyl), an optionally substituted heterocyclicgroup (e.g., chloropyrazolyl), a C₁₋₆ alkoxy-C₁₋₆ alkyl group (e.g.,methoxymethyl) or a C₁₋₆ alkyl-amino group (e.g., isopropylamino). Thenumber of substituents is for example 1 or 2.

In some embodiments of the inventive compounds of formula (1), R² and R³are the same or different and each is —(CH₂)_(p)—X₁—(CH₂)_(q)-A²,wherein each symbol is as defined above, or—(CH₂)_(m8)—X₈—(CH₂)_(n8)—R²⁷, wherein each symbol is as defined above,preferably, one of them is —(CH₂)_(m8)—X₈—(CH₂)_(n8)—R²⁷ (preferablyhydrogen atom or a C₁₋₆ alkyl group optionally substituted by hydroxylgroups), and the other is —(CH₂)_(p)—X₁—(CH₂)_(q)-A², wherein eachsymbol is as defined above.

p and q are the same or different and each is for example 0 or aninteger ranging from 1 to 2, preferably 0.

X₁ is for example a single bond, —O—, —N(R⁵)— (preferably R⁵ is ahydrogen atom, a C₁₋₆ alkyl group optionally substituted by hydroxylgroups (e.g., methyl)), —S(O)_(m1), (preferably m1 is 0), —CO—, —COO—,—OCO—, —N(R⁵)CO— (preferably R⁵ is a hydrogen atom), —OCON(R⁵)—(preferably R⁵ is a hydrogen atom) or —S(O)_(m1)—(CH₂)_(n1)—CO—(preferably m1 is 0 and n1 is 1), preferably a single bond.

A² is for example a group of the following formula

wherein each symbol is as defined above.

The C₃₋₁₄ hydrocarbon ring group at ring A¹² is for example a C₆₋₁₄ arylgroup (preferably phenyl) or a C₃₋₈ cycloalkyl group (preferablycyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl).

The heterocyclic group at ring A¹² is for example a saturated monocyclicheterocyclic group (e.g., pyrrolidinyl, piperidinyl, piperazinyl,tetrahydrofuryl, 2-oxazolidinyl, morpholinyl, 3-oxo-morpholinyl) or anunsaturated monocyclic heterocyclic group (e.g., pyrazolyl, pyridyl,imidazolyl, thiazolyl, isooxazolyl).

The ring A is optionally substituted by 1 to 5 groups of the formula“—(CH₂)_(m7)—X₇—(CH₂)_(n7)—R²⁶”, which are the same or different. Thenumber of substituents is for example 1 or 2.

m7 and n7 are the same or different and each is for example 0 or aninteger ranging from i to 2, preferably 0.

X₇ is for example a single bond, —O—, —N(R⁵)—, —S(O)_(m1)—, —CO—, —COO—,—OCO—, —CON(R⁵)—, —N(R⁵)CO—, —N(R⁵)SO₂—, —OCON(R⁵)— or —N(R⁵)COO—(preferably R⁵ is a hydrogen atom and a C₁₋₆ alkyl group optionallysubstituted by hydroxyl groups (e.g., methyl), and m1 is 2), preferablya single bond.

R²⁶ is for example

(a) a halogen atom (e.g., a chlorine atom, a bromine atom, a fluorineatom),(b) a hydroxyl group,(c) a nitro group,(d) a carboxyl group,(e) an amino group,(f) a halogenated C₁₋₆ alkyl group (e.g., trifluoromethyl),(g) a C₁₋₆ alkyl group optionally substituted by hydroxyl groups (e.g.,methyl, isobutyl, hydroxymethyl, 1-hydroxy-1-methyl-ethyl,2-hydroxy-1,1-dimethylethyl),(h) a C₁₋₆ alkoxy group optionally substituted by hydroxyl groups,(e.g., methoxy, tert-butoxy),(i) a mono(C₁₋₆ alkyl)amino group (e.g., methylamino, t-butylamino),(j) a di(C₁₋₆ alkyl)amino group (e.g., dimethylamino),(k) a C₁₋₆ alkylsulfonyl group (e.g., methanesulfonyl),(l) a C₃₋₁₄ hydrocarbon ring group optionally substituted by 1 to 5substituent(s) selected from the above-mentioned group B,

-   -   wherein the “C₃₋₁₄ hydrocarbon ring group” is for example a        C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) or a C₆₋₁₄ aryl group        (e.g., phenyl), the substituent thereof is for example a halogen        atom (e.g., chlorine atom), a hydroxyl group or a C₁₋₆ alkyl        group optionally substituted by hydroxyl groups (e.g., methyl),        and the number of substituents is for example 1;        or        (m) a heterocyclic group optionally substituted by 1 to 5        substituent(s) selected from the above-mentioned group B,    -   wherein the “heterocyclic group” is for example a saturated        monocyclic heterocyclic group (e.g., piperidinyl, pyrrolidinyl,        2-oxo-pyrrolidinyl, morpholinyl, piperazinyl), an unsaturated        monocyclic heterocyclic group (e.g., pyridyl, pyrazolyl,        thiazolyl, imidazolyl, 4,5-dihydro-oxazolyl) or the like, the        substituent thereof is for example a hydroxyl group, a C₁₋₆        alkyl group optionally substituted by hydroxyl groups (e.g.,        methyl, hydroxymethyl, isopropyl) or a C₁₋₆ alkoxy-carbonyl        group (e.g., tert-butoxy carbonyl), and the number of        substituents is for example 1.

The ring A¹² is may take together with a group of the formula“—(CH₂)_(m7)—X₇—(CH₂)_(n7)—R²⁶” to form an optionally substituted fusedring group. The optionally substituted fused ring group is for examplethe above-defined “optionally substituted fused C₆₋₁₄ hydrocarbon ringgroup”, the above-defined “optionally substituted fused heterocyclicgroup” or the like.

The “fused C₆₋₁₄ hydrocarbon ring group” in the “optionally substitutedfused C₆₋₁₄ hydrocarbon ring group” is for example 9H-fluorenyl or9-oxo-9H-fluorenyl. The substituent thereof is for example a halogenatom (e.g., a chlorine atom, a bromine atom, a fluorine atom), and thenumber of substituents is for example 1.

The “fused heterocyclic group” in the “optionally substituted fusedheterocyclic group” is for example tetrahydroisoquinolyl or4-oxo-4H-benzo[d][1,2,3]triazinyl. The substituent thereof is forexample a C₁₋₆ alkyl group (e.g., methyl, isopropyl) or a C₁₋₆ alkylgroup substituted by C₆₋₁₄ aryl groups (e.g., benzyl), and the number ofsubstituents is for example 1.

m8 and n8 in —(CH₂)_(m8)—X₈—(CH₂)_(n8)—R²⁷ are for example the same ordifferent and each is 0 or an integer ranging from 1 to 2.

The X₈ is for example a single bond, —O—, —N(R⁵)—, —S(O)_(m1)—, —OCO—,—N(R⁵)CO—, —OCON(R⁵)— or —S(O)_(m1)(CH₂)_(n1)—CO— (preferably R⁵ is ahydrogen atom, a C₁₋₆ alkyl group optionally substituted by hydroxylgroups (e.g., methyl), m1 is 0, 1 or 2 and n1 is 1).

R²⁷ is for example

(a) a hydrogen atom(b) a hydroxyl group,(c) a carboxyl group,(d) an amino group,(e) a C₁₋₆ alkyl group optionally substituted by hydroxyl groups (e.g.,methyl, ethyl, isopropyl, t-butyl, hydroxymethyl, 2-hydroxyethyl),(f) a C₂₋₆ alkenyl group optionally substituted by halogen atoms (e.g.,vinyl),(g) a C₁₋₆ alkoxy group optionally substituted by hydroxyl groups,(e.g., methoxy, ethoxy, isopropoxy, t-butoxy),(h) a mono(C₁₋₆ alkyl)amino group (e.g., ethylamino),or(i) a di(C₁₋₆ alkyl)amino group (e.g., dimethylamino, diethylamino).

A² and R²⁷ may be taken together to form an optionally substituted fusedring group. R²⁶ may be linked with R²⁷, together with the ring A¹² toform an optionally substituted fused ring group. The optionallysubstituted fused ring group is for example the above-defined“optionally substituted fused C₆₋₁₄ hydrocarbon ring group”, theabove-defined “optionally substituted fused heterocyclic group” or thelike. Examples thereof include 1,2,3,4-tetrahydroisoquinoline and thelike. The substituent thereof is for example a substituent selected fromthe above-mentioned group C, preferably a C₂₋₆ acyl group (e.g.,acetyl). The number of substituents is for example 1.

R² and R³ may be taken together with a carbon atom bonded thereto toform the following ring

wherein each symbol is as defined above.

m13 is for example an integer of 1 to 4, preferably 1.

Provided that R² and R³ are not hydrogen atoms at the same time.

In some embodiments of the inventive compounds of formula (1), R²⁰ andR²¹ are the same or different and each is (CH₂)_(m10)X₁₀—(CH₂)_(n10)-A³, wherein each symbol is as defined above, or—(CH₂)_(m12)—X₂—(CH₂)_(n12)—R³, wherein each symbol is as defined above,preferably —(CH₂)_(m12)—X₁₂—(CH₂)_(n12)—R³⁰ (more preferably a hydrogenatom or a C₁₋₆ alkyl group optionally substituted by hydroxyl groups).

m10 and n10 are the same or different and each is for example 0 or aninteger ranging from 1 to 2, preferably 0.

X₁₀ is for example, a single bond.

A³ is for example, a group of the following formula

wherein each symbol is as defined above.

m12 and n12 are the same or different and each is for example 0 or aninteger ranging from 1 to 2, preferably 0.

X₁₂ is for example a single bond.

R³⁰ is for example

(a) a hydrogen atom,(b) a C₁₋₆ alkyl group optionally substituted by hydroxyl groups (e.g.,methyl, ethyl, 2-hydroxymethyl)or(c) a C₁₋₆ alkoxy-C₁₋₆ alkyl group (e.g., methoxymethyl).

A², R³⁰ and the cyclopropane ring may be taken together to form anoptionally further substituted fused ring. R²⁶ may be linked with R³⁰,together with the ring A¹² and the cyclopropane ring to form anoptionally further substituted fused ring.

The “fused ring” is for example a fused C₆₋₁₄ hydrocarbon ring in theabove-defined fused C₆₋₁₄ hydrocarbon ring group or a fused heterocyclicring in the above-defined fused heterocyclic group, wherein theabove-defined C₃₋₁₄ hydrocarbon ring group and/or the above-definedheterocyclic group are/is fused with the cyclopropane ring, or the like.Examples thereof include1,1a,2,3,4,8b-hexahydro-benzo[a]cyclopropa[c]cycloheptene,1,1a,6,6a-tetrahydro-cyclopropa[a]indene,1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene,1a,2,3,8b-tetrahydro-1H-4-oxa-benzo[a]cyclopropa[c]cycloheptene,1,1a,2,3,4,8b-hexahydro-4-aza-benzo[a]cyclopropa[c]cycloheptene and thelike. The “fused ring” is optionally further substituted, and thesubstituent thereof is for example a substituent selected from theabove-mentioned group C, preferably a hydroxyl group or a C₂₋₆ acylgroup (e.g., acetyl). The number of substituents is for example 1.

R²⁰ and R²¹ may be taken together with a carbon atom bonded thereto toform the following ring

wherein each symbol is as defined above.

m14 is for example an integer of 1 to 4, preferably 1.

In some embodiments of the inventive compounds of formula (1), R⁴ is forexample —CO₂R⁹, —C(O)NHOR⁹ or —(CH₂)_(r1)—R⁵⁰, preferably —CO₂R⁹,wherein each symbol is as defined above.

R⁹ is for example a hydrogen atom or —(CH₂)_(m9)—X₉—(CH₂)_(n9)—R²⁸,wherein each symbol is as defined above.

m9 and n9 are the same or different and each is for example 0 or aninteger ranging from 1 to 2.

X₉ is for example a single bond.

R²⁸ is for example a C₃₋₁₄ hydrocarbon ring group optionally substitutedby 1 to 5 substituent(s) selected from the above-mentioned group B, aheterocyclic group optionally substituted by 1 to 5 substituent(s)selected from the above-mentioned group B or the like.

r1 is for example 0 or an integer ranging from 1 to 2.

The “optionally substituted C₃₋₁₄ hydrocarbon ring group” at R²⁸ and R⁵⁰is for example the above-defined “optionally substituted fused C₃₋₁₄hydrocarbon ring group” or the like.

The “optionally substituted heterocyclic group” at R²⁸ and R⁵⁰ is forexample the above-defined “optionally substituted heterocyclic group” orthe like. Examples thereof include 1-hydroxy-1H-pyridin-2-one,3-hydroxy-1H-pyridin-2-one, 3-hydroxy-1,2-dimethyl-1H-pyridin-4-one,3-hydroxy-pyran-4-one, 3-hydroxy-2-methyl-pyran-4-one,3-hydroxy-1H-pyridin-2-one, 1-hydroxy-1H-pyridine-2-thione,3-hydroxy-1,2-dimethyl-1H-pyridine-4-thione,3-hydroxy-1H-pyridine-2-thione, 3-hydroxy-pyran-4-thione,3-hydroxy-2-methyl-pyran-4-thione, 3H-[1,3,4]thiadiazole-2-thione,barbituric acid, 2-thioxo-thiazolidin-4-one, thiazolidine-2,4-dione,imidazolidine-2,4-dione, 6H-1,3,4-thiazine, nitropyrimidine and thelike.

R⁹ of —C(O)NHR⁹, A² and the cyclopropane ring may be taken together toform an optionally further substituted fused ring. R²⁶ may be linkedwith R⁹ of —C(O)NHR⁹ or R³⁰, together with the ring A¹² and thecyclopropane ring to form an optionally further substituted fused ring.

The “fused ring” is for example a fused C₆₋₁₄ hydrocarbon ring in theabove-defined fused C₆₋₁₄ hydrocarbon ring group or a fused heterocyclicring in the above-defined fused heterocyclic group, wherein theabove-defined C₃₋₁₄ hydrocarbon ring group and/or the above-definedheterocyclic group are/is fused with the cyclopropane ring, or the like.Examples thereof include2-oxo-1,2,3,7b-tetrahydro-3-aza-cyclopropa[a]naphthalene,2-oxo-2,3,4,8b-tetrahydro-1H-3-aza-benzo[a]cyclopropa[c]cycloheptene andthe like. The “fused ring” is optionally further substituted, and thesubstituent thereof is for example a substituent selected from theabove-mentioned group C. The number of substituents is for example 1.

R⁹ of —CO₂R⁹, R²⁰ and the cyclopropane ring may be taken together toform an optionally further substituted fused ring. The “fused ring” isfor example a fused C₆₋₁₄ hydrocarbon ring in the above-defined fusedC₆₋₁₄ hydrocarbon ring group or a fused heterocyclic ring in theabove-defined fused heterocyclic group, wherein the above-defined C₃₋₁₄hydrocarbon ring group and/or the above-defined heterocyclic groupare/is fused with the cyclopropane ring, or the like. Examples thereofinclude 2-oxo-3-oxa-bicyclo[3.1.0]hexyl and the like. The “fused ring”is optionally further substituted, and the substituent thereof is forexample a substituent selected from the above-mentioned group C. Thenumber of substituents is for example 1.

As the compound represented by the formula (1), the following compoundis preferable.

[Compound A]

A compound wherein

R¹ is the formula —(CH₂)_(m)—X—(CH₂)_(n)-A¹ wherein each symbol is asdefined above, preferably m and n are 0, X is a single bond, and A¹ is agroup of the following formula:

wherein ring A¹⁰, r and R²² are as defined above,

R²³ is

wherein each symbol is as defined above, preferably m5 and n5 are 0 andXs is a single bond;

R² is (CH₂)_(p)—X₁—(CH₂)_(q)-A², wherein each symbol is as definedabove, preferably p and q are 0, X₁ is a single bond, and A² is a groupof the following formula:

wherein each symbol is as defined above;

A³ at R²⁰ and R²¹ is a group of the following formula

wherein each symbol is as defined above; and

R⁴ is —CO₂R⁹ or —C(O)NHOR⁹, wherein each symbol is as defined above,preferably R⁹ is hydrogen atom.

As the compound represented by the formula (1), the compound representedby the following formula (1′) is also preferable:

whereinR¹ is selected from(1) a substituted C₁₋₆ alkyl group,and(2) —(CH₂)_(m)—X—(CH₂)_(n)-A¹,whereinm and n are the same or different and each is selected from 0 and aninteger ranging from 1 to 6,X is selected from a single bond, a C₁₋₆ alkylene group, a C₂₋₆alkenylene group, a C₂₋₆ alkynylene group, —O—, —N(R⁵)—, —S(O)_(m1)—,—CO—, —CON(R⁵)—, —N(R⁵)CO—, —SO₂N(R⁵)—, —N(R⁵)SO₂—, N(R⁵)CON(R⁶)—,—N—(R⁵) SO₂N(R⁶)—, —OCON(R⁵)— and —N(R⁵)COO—, whereinR⁵ and R⁶ are the same or different and each is selected from a hydrogenatom and a C₁₋₆ alkyl group,m1 is selected from 0 and an integer ranging from 1 to 2,A¹ is selected from a substituted C₃₋₁₄ hydrocarbon ring group and asubstituted heterocyclic group;R² and R³ are the same or different and each is selected from(1) a hydrogen atom,(2) a C₁₋₆ alkyl group,(3) a halogenated C₁₋₆ alkyl group,and(4) —(CH₂)_(p)—X₁—(CH₂)_(q)-A² provided that R² and R³ are not hydrogenatoms at the same time,whereinp and q are the same or different and each is selected from 0 and aninteger ranging from 1 to 6,X₁ is selected from a single bond, a C₁₋₆ alkylene group, a C₂₋₆alkenylene group, a C₂₋₆ alkynylene group, —O—, N(R⁷)—, —S(O)_(m2)—,—CO—, —CON(R⁷)—, —N(R⁷)CO—, —SO₂N(R⁷)—, —N(R⁷) SO₂—, N(R⁷)CON(R⁸)—,—N(R⁷) SO₂N(R⁸)—, —OCON(R⁷)— and —N(R⁷)COO—,whereinR⁷ and R⁸ are the same or different and each is selected from a hydrogenatom and a C₁₋₆alkyl group,m2 is selected from 0 and an integer ranging from 1 to 2,r is selected from 0 and an integer ranging from 1 to 2, andA² is selected from an optionally substituted C₃₋₁₄ hydrocarbon ringgroup and an optionally substituted heterocyclic group; andR⁴ is selected from

(1) —CO₂R⁹, (2) —C(O)NHOR⁹, (3) —C(O)NH—SO₂—R⁹, (4) —C(O)NHR⁹, (5) —SH,(6) —CH₂CO₂R⁹, (7) —C(O)R⁹, (8) —N(OH)COR⁹, (9) —SN₂H₂R⁹, (10) —SONHR⁹,(11) —CH₂CO₂H, (12) —PO(OH)₂, (13) —PO(OH)NHR⁹, (14) —CH₂SH

and

(15) —CH₂OH

whereinR⁹ is selected from a hydrogen atom, an optionally substituted C₁₋₁₀alkyl group and an optionally substituted C₆₋₁₄ aryl-C₁₋₆ alkyl group.

In some embodiments of the inventive compounds of formula (1′), R¹ is—(CH₂)_(m)—X—(CH₂)_(n)-A¹ wherein each symbol is as defined above.

m and n are the same or different and each is selected from 0 and aninteger ranging from 1 to 2, preferably 0.

X is for example a single bond.

A¹ is for example

(1) an optionally substituted fused C₆₋₁₄ hydrocarbon ring group;

such as an optionally substituted 9H-fluorenyl or an optionallysubstituted 9-oxo-9H-fluorenyl. The substituent thereof is for exampleat least one halogen atom (e.g., a chlorine atom, a bromine atom, afluorine atom), and the number of substituents is for example 1.Examples thereof include 9H-fluoren-2-yl, 9-oxo-9H-fluoren-2-yl,7-bromo-9H-fluoren-2-yl, 7-fluoro-9H-fluoren-2-yl,7-chloro-9H-fluoren-2-yl and the like.

(2) an optionally substituted fused heterocyclic group;

such as an optionally substituted benzofuranyl or optionally substituteddibenzofuranyl. The substituent thereof is for example at least onehalogen atom (e.g., a chlorine atom), and the number of substituents isfor example 1. Examples thereof include 2-benzofuran-2-yl,dibenzofuran-2-yl, dibenzofuran-3-yl, 7-chloro-dibenzofuran-3-yl,8-chloro-dibenzofuran-3-yl and the like.

or(3) —V—W-Z, wherein each symbol is as defined above. The optionallysubstituted C₃₋₁₄ hydrocarbon ring group at V is for example a C₆₋₁₄aryl group (e.g., phenyl).

The optionally substituted heterocyclic group at V is for example anoptionally substituted saturated monocyclic heterocyclic group (e.g.,piperazinyl) or an optionally substituted unsaturated monocyclicheterocyclic group (e.g., thienyl, methylthienyl, pyrazolyl, thiazolyl).The substituent thereof is for example a C₁₋₆ alkyl group (e.g.,methyl).

t and u at W represented by —(CH₂)_(t)—X₂—(CH₂)_(u)— are for example thesame or different and each is 0 or an integer ranging from 1 to 2, morepreferably 0.

The X₂ at W is for example selected from a single bond, a C₂₋₆alkynylene group and —O—, preferably a single bond.

The C₂₋₆ alkynylene group at X₂ is for example ethynylene.

Z is for example selected from an optionally substituted C₁₋₆ alkylgroup, a halogen atom, an optionally substituted C₃₋₁₄ hydrocarbon ringgroup and an optionally substituted heterocyclic group.

The optionally substituted C₁₋₆ alkyl group at Z is for example selectedfrom a C₁₋₆ alkyl group substituted by a hydroxyl group (e.g.,1-hydroxyethyl).

The halogen atom at Z is for example selected from a chlorine atom, abromine atom and a fluorine atom.

The optionally substituted C₃₋₁₄ hydrocarbon ring group at Z is forexample selected from an optionally substituted C₆₋₁₄ aryl group, suchas phenyl. The substituent thereof is for example selected from ahalogen atom (e.g., a chlorine atom, a bromine atom), a C₁₋₆ alkoxygroup (e.g., methoxy) and a di(C₁₋₆ alkyl)amino group (e.g.,dimethylamino), and the number of the substituent is for example 1 or 2.Examples thereof include phenyl, chlorophenyl (e.g., 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl), dichlorophenyl (e.g.,2,4-dichlorophenyl, 3,4-dichlorophenyl), bromophenyl, methoxyphenyl(e.g., 4-methoxyphenyl), dimethylaminophenyl and the like.

The optionally substituted heterocyclic group at Z is for exampleselected from an optionally substituted unsaturated monocyclicheterocyclic group (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,tetrazolyl, thiophenyl, thiazolyl, pyridazinyl, isooxazolyl, pyridyl).The substituent thereof is for example selected from a halogen atom(e.g., a chlorine atom, a bromine atom), a C₁₋₆ alkyl group (e.g.,methyl, ethyl, propyl, isopropyl), a halogenated C₁₋₁₆ alkyl group(e.g., trifluoromethyl, pentafluoroethyl), a C₁₋₆ alkoxy group (e.g.,methoxy), a di(C₁₋₆ alkyl)amino group (e.g., dimethylamino), a carboxylgroup and a C₆₋₁₄ aryl group (e.g., phenyl), and the number ofsubstituents is for example 1 or 2. Examples thereof include5-trifluoromethyl-1,2,4-oxadiazol-3-yl,5-pentafluoroethyl-1,2,4-oxadiazol-3-yl, 5-methyl-1,2,4-oxadiazol-3-yl,5-phenyl-1,2,4-oxadiazol-3-yl, 5-phenyl-1,3,4-oxadiazol-2-yl,2-methyl-2H-tetrazol-5-yl, 2-ethyl-2H-tetrazol-5-yl,2-propyl-2H-tetrazol-5-yl, 2-isopropyl-2H-tetrazol-5-yl, thiophen-2-yl,thiophen-3-yl, 4-methyl-thiophen-2-yl, 5-carboxy-thiophen-2-yl,2-ethyl-thiazol-4-yl, 2-methyl-thiazol-4-yl, 6-chloro-pyridazin-3-yl,isoxazol-3-yl, 5-trifluoromethyl-isoxazol-3-yl, 5-chloropyridin-2-yl andthe like.

In some embodiments of the inventive compounds of formula (1′), R² andR³ are the same or different and each is selected from a hydrogen atom,a C₁₋₆ alkyl group and —(CH₂)_(p)—X₁—(CH₂)_(q)-A², in one embodiment,one of them is a hydrogen atom or a C₁₋₆ alkyl group, and the other is—(CH₂)_(p)—X₁—(CH₂)_(q)-A².

The C₁₋₆ alkyl group at R² and R³ is for example methyl.

p and q are the same or different and each is for example selected from0 and an integer ranging from 1 to 2, preferably 0.

X₁ is for example a single bond.

A² is for example

(1) an optionally substituted fused C₆₋₁₄ hydrocarbon ring group;

such as an optionally substituted 9H-fluorenyl or an optionallysubstituted 9-oxo-9H-fluorenyl. The substituent thereof is for exampleat least one halogen atom (e.g., a chlorine atom, a bromine atom, afluorine atom), and the number of substituents is for example 1.Examples thereof include 9H-fluoren-2-yl, 9-oxo-9H-fluoren-2-yl,7-bromo-9H-fluoren-2-yl, 7-fluoro-9H-fluoren-2-yl,7-chloro-9H-fluoren-2-yl and the like.

(2) an optionally substituted fused heterocyclic group;

such as an optionally substituted tetrahydroisoquinolyl. The substituentthereof is for example selected from a C₁₋₆ alkyl group (e.g., methyl,isopropyl) and a C₁₋₆ alkyl group substituted by a C₆₋₁₄ aryl group(e.g., benzyl), and the number of substituents is for example 1.Examples thereof include 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl,2-isopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl,2-benzyl-1,2,3,4-tetrahydroisoquinolin-7-yl and the like.

or

(3) —V¹—W¹-Z¹

V¹ is an optionally substituted C₃₋₁₄ hydrocarbon ring group or anoptionally substituted heterocyclic group;

W¹ is —X₃—(CH₂)_(t1)—X₄—(CH₂)_(u1)—

wherein

t1 and u1 are the same or different and each is selected from 0 and aninteger ranging from 1 to 6,

X₃ and X₄ are the same or different and each is selected from a singlebond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group, a C₂₋₆ alkynylenegroup, —O—, —N(R¹²)—, —S(O)_(m4)—, —CO—, —CON(—R¹²)—, —N(R¹²)CO—,—SO₂N(R¹²)—, —N(R¹²)SO₂—, —N(R¹²)CON(R¹³)—, —N(R¹²)SO₂N(R¹³)—,—OCON(R¹²)— and —N(R¹²)COO—,

-   -   wherein R¹² and R¹³ are the same or different and each is        selected from a hydrogen atom and a C₁₋₆ alkyl group, and m4 is        selected from 0 and an integer ranging from 1 to 2,

and

Z¹ is selected from an optionally substituted C₁₋₆ alkyl group, ahalogen atom, a nitro group, a cyano group, a C₁₋₆ alkoxy group, ahydroxyl group, a halogenated C₁₋₆ alkyl group, a halogenated C₁₋₆alkoxy group, a carboxyl group, a C₁₋₆ alkoxy-carbonyl group, an aminogroup, a mono(C₁₋₆ alkyl)amino group, a di(C₁₋₆ alkyl)amino group, anoptionally substituted C₃₋₁₄ hydrocarbon ring group and an optionallysubstituted heterocyclic group.

The optionally substituted C₃₋₁₄ hydrocarbon ring group at V¹ ispreferably an optionally substituted C₆₋₁₄ aryl group (for examplephenyl) or a C₃₋₈ cycloalkyl group (for example cyclohexyl).

The optionally substituted heterocyclic group at V¹ is for exampleoptionally substituted saturated monocyclic heterocyclic group (e.g.,piperidinyl).

t1 and u1 at W¹ are the same or different and each is for exampleselected from 0 and an integer ranging from 1 to 2, preferably 0.

X₃ and X₄ at W¹ are the same or different and each is for exampleselected from a single bond, —O—, —CO—, —N(R¹²)—, —CON(R¹²)—,—N(R¹²)CO—, —N(R¹²)SO₂— and —N(R¹²)COO—, wherein R¹² is for exampleselected from a hydrogen atom and methyl.

Z¹ is for example selected from an optionally substituted C₁₋₆ alkylgroup, a halogen atom, a nitro group, a hydroxyl group, a halogenatedC₁₋₆ alkyl group, an amino group, a di(C₁₋₆ alkyl)amino group, anoptionally substituted C₃₋₁₄ hydrocarbon ring group and an optionallysubstituted heterocyclic group.

The optionally substituted C₁₋₆ alkyl group at Z¹ is for example methylor isobutyl.

The halogen atom at Z¹ is for example a bromine atom.

The C₁₋₆ alkoxy group at Z¹ is for example tert-butoxy.

The halogenated C₁₋₆ alkyl group at Z¹ is for example trifluoromethyl.

The di(C₁₋₆ alkyl)amino group at Z¹ is for example dimethylamino.

The optionally substituted C₃₋₁₄ hydrocarbon ring group at Z¹ is forexample an optionally substituted C₆₋₁₄ aryl group, for example phenyl.The substituent thereof is for example at least one halogen atom (e.g.,a chlorine atom), and the number of substituents is for example l.Examples thereof include phenyl, 4-chlorophenyl and the like.

The optionally substituted heterocyclic group at Z¹ is for exampleselected from an optionally substituted saturated monocyclicheterocyclic group and an optionally substituted unsaturated monocyclicheterocyclic group.

The optionally substituted saturated monocyclic heterocyclic group at Z¹is for example selected from an optionally substituted-piperidinylgroup, an optionally substituted pyrrolidinyl group, an optionallysubstituted morpholinyl group and an optionally substituted piperazinylgroup. The substituent thereof is for example selected from a C₁₋₆ alkylgroup (e.g., methyl) and C₁₋₆ alkoxy-carbonyl group (e.g.,tert-butoxycarbonyl group), and the number of substituents is forexample 1. Examples thereof include 1-methyl-piperidin-4-yl,1-tert-butoxycarbonyl group-piperidin-4-yl, pyrrolidin-1-yl,morpholin-4-yl, 4-methyl-piperazin-1-yl and the like.

The optionally substituted saturated monocyclic heterocyclic group at Z¹is for example selected from an optionally substituted pyridyl group, anoptionally substituted pyrazolyl group and an imidazolyl group. Thesubstituent thereof is for example a C₁₋₆ alkyl group (e.g., methyl),and the number of substituents is for example 1. Examples thereofinclude pyridin-3-yl, pyrazol-1-yl, 3H-imidazol-4-yl, 1H-imidazol-2-yl,1-methyl-1H-imidazol-2-yl and the like.

In the compounds represented by the formula (1′), R⁴ is for exampleselected from —CO₂R⁹ and —C(O)NHOR⁹, such as —CO₂R⁹ wherein R⁹ is forexample a hydrogen atom.

The “pharmaceutically acceptable salt” may be any as long as it forms anon-toxic salt with a compound of the above-mentioned formula (1). Suchsalt can be obtained by reacting the compound with an inorganic acidsuch as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromicacid and the like; or an organic acid such as oxalic acid, malonic acid,citric acid, fumaric acid, lactic acid, malic acid, succinic acid,tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid,ascorbic acid, methylsulfonic acid, benzylsulfonic acid and the like; oran inorganic bases such as sodium, potassium, lithium, calcium,magnesium, ammonium and the like; or an organic bases such asmethylamine, diethylamine, triethylamine, triethanolamine,ethylenediamine, tris(hydroxymethyl)methylamine, guanidine, choline,cinchonine N-methyl-D-glucamine and the like; or an amino acid such aslysine, histidine, arginine, alanine and the like. The present inventionencompasses water-retaining product, hydrate and solvate of eachcompound.

The compounds of the above-mentioned formula (1) have various isomers.For example, E compound and Z compound are present as geometric isomers,and when the compound has an asymmetric carbon, an enantiomer and adiastereomer are present due to the asymmetric carbon. A tautomer may bealso present. The present invention encompasses all of these isomers andmixtures thereof.

The present invention also encompasses prodrug and metabolite of thecompound represented by the formula (1).

The “prodrug” means a derivative having a chemically modified drugmolecule, which does not show physiological activity by itself, butwhich shows inherent efficacy by reverting to the original compound in abody after administration. The “prodrug” in the present invention meansa derivative of cyclopropane compound (1) having a group capable ofchemical or metabolic decomposition and showing a pharmaceuticalactivity by hydrolysis or solvolysis or by decomposition underphysiological condition. For example, those wherein a hydroxyl group ofthe compound is substituted by —CO-alkyl group, —CO₂-alkyl group,—CONH-alkyl group, —CO-alkenyl, —CO₂-alkenyl, —CONH-alkenyl, —CO-arylgroup, —CO₂-aryl group, —CONH-aryl group, —CO-heterocyclic ring,—CO₂-heterocyclic ring, —CONH-heterocyclic ring (the alkyl group,alkenyl, aryl group, heterocyclic ring are optionally substituted byhalogen atom, alkyl group, hydroxyl group, alkoxy group, carboxyl group,amino group, amino acid residue, —PO₃H₂, —SO₃H, —OPO₃H₂, —OSO₃H, and thelike), or —CO-polyethylene glycol residue, —CO₂-polyethylene glycolresidue, —CO-polyethylene glycol mono alkyl ether residue,—CO₂-polyethylene glycol mono alkyl ether residue, —PO₃H₂, saccharides(e.g., glucose), or other known macromolecule for a prodrug and thelike;

those wherein an amino group of the compound is substituted by —CO-alkylgroup, —CO₂-alkyl group, —CO-alkenyl, —CO₂-alkenyl, —CO₂-aryl group,—CO-aryl group, —CO-heterocyclic ring, —CO₂-heterocyclic ring (the alkylgroup, alkenyl, aryl group, heterocyclic ring are optionally substitutedby halogen atom, alkyl group, hydroxyl group, alkoxy group, carboxylgroup, amino group, amino acid residue, —PO₃H₂, —SO₃H, —OPO₃H₂, —OSO₃H,and the like), or —CO-polyethylene glycol residue, —CO₂-polyethyleneglycol residue, —CO-polyethylene glycol mono alkyl ether residue,—CO₂-polyethylene glycol mono alkyl ether residue, —PO₃H₂, saccharides(e.g., glucose), or other known macromolecule for a prodrug and thelike; and

those wherein a carboxyl group of the compound is substituted by alkoxygroup, aryloxy group (the alkoxy group, aryloxy group are optionallysubstituted by halogen atom, alkyl group, hydroxyl group, alkoxy group,carboxyl group, amino group, amino acid residue, —PO₃H₂, —SO₃H, —OPO₃H₂,—OSO₃H, and the like), or polyethylene glycol residue, polyethyleneglycol mono alkyl ether residue, saccharides (e.g., glucose), or otherknown macromolecule for a prodrug and the like are mentioned as examplesof embodiments of the present invention.

These prodrugs can be produced, for example, according to a method knownper se by one of skill in the pertinent field, such as esterification,acylation, alkoxycarbonylation, and the like.

When the inventive compound is used as a pharmaceutical preparation, theinventive compound is generally admixed with pharmaceutically acceptablecarriers, excipients, diluents, fillers, disintegrators, stabilizers,preservatives, buffers, emulsifiers, aromatics, coloring agents,sweeteners, thickeners, correctives, solubilizers, and other additivessuch as water, vegetable oil, alcohol such as ethanol, benzyl alcoholand the like, polyethylene glycol, glycerol triacetate, gelatin,lactose, carbohydrate such as starch and the like, magnesium stearate,talc, lanolin, petrolatum and the like, and prepared into a dosage form,for example, of tablets, pills, powders, granules, suppositories,injections, eye drops, liquids, capsules, troches, aerosols, elixirs,suspensions, emulsions, syrups and the like, which can be administeredsystemically or topically and orally or parenterally.

While the dose of the inventive compound varies depending on the age,body weight, general condition, treatment effect, administration routeand the like, it is generally from 1 mg to 1000 mg for an adult perdose, which is given one to several times a day.

The inventive compound (1) can be administered to mammals (human, mouse,rat, rabbit, dog, cat, cattle, pig, monkey, etc.) as an aggrecanaseinhibitor, an MMP inhibitor, a prophylactic or therapeutic agent forosteoarthritis (OA), a prophylactic or therapeutic agent for rheumatoidarthritis (RA), a prophylactic or therapeutic agent for a disordermediated by aggrecanase, such as joint injury, reactive arthritis,cancer, asthma, allergic reaction, chronic pulmonary emphysema, fibroidlung, acute respiratory distress (ARDS), lung infection, interstitialpneumonia, bone resorption disorder, and the like.

The compound (1) of the present invention can be administered to mammalsalong with other therapeutic agents for osteoarthritis, for the purposeof prevention or treatment of osteoarthritis. The compound (1) of thepresent invention can be also administered to mammals along with othertherapeutic agents for rheumatoid arthritis, for the purpose ofprevention or treatment of rheumatoid arthritis.

“Prevention” include, for example, both preventing recurrence of thedisease and preventing initial occurrence of the disease.

In the case of combined administration, the compound of the presentinvention can be administered simultaneously with other therapeuticagents for osteoarthritis or other therapeutic agents for rheumatoidarthritis (hereinafter combination drug) or administered at certain timeintervals. In the case of combined administration, a pharmaceuticalcomposition containing the compound of the present invention and acombination drug can be administered. Alternatively, a pharmaceuticalcomposition containing the compound of the present invention and apharmaceutical composition containing a combination drug may beadministered separately. The administration route may be the same ordifferent.

In the case of a combined administration, the compound of the presentinvention can be administered once a day or several times a day in asingle dose of 1 mg to 1000 mg, or may be administered in a smallerdose. The combination drug can be administered in a dose generally usedfor the prevention or treatment of osteoarthritis or rheumatoidarthritis or in a smaller dose.

In addition, a compound having aggrecanase inhibitory activity or MMPinhibitory activity as does the compound (1) of the present invention, aprodrug thereof and a pharmaceutically acceptable salt thereof can beused as prophylactic or therapeutic agents for diseases mediated byaggrecanase, such as osteoarthritis, rheumatoid arthritis, and the like.

Examples of the production method of the compound (1) of the presentinvention are given in the following. However, the production method ofthe compound of the present invention is not limited to these examples.

It is also possible to previously protect, as necessary, the functionalgroups other than those involved in the reactions to be mentioned below,and to deprotect them at a later stage.

The treatment after reaction in each step may be a conventional one, forwhich typical methods, such as isolation and purification,crystallization, recrystallization, column chromatography, preparativeHPLC and the like, can be appropriately selected and combined.

The compound (2), which is a starting material in the followingproduction methods, is commercially available or can be easilysynthesized by a method known per se by one of skill in the art.

Production Method 1

This production method is a production method for compound (1) whereinR² is a hydrogen atom and R⁴ is a hydroxyl group or a hydroxyaminogroup.

wherein R¹ and R³ are as defined above and Z is a protective group ofamino group (e.g., benzyloxycarbonyl, tert-butoxycarbonyl, etc.)

Step A-1

General deprotection is performed. A compound of the formula (2) isreacted in the presence of an acid in a solvent to give a compound ofthe formula (3).

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, etc.; etc. can be mentioned, which maybe used alone or in combination. A preferable solvent in this reactionis dioxane.

As the acid to be used for the reaction is, for example, inorganic acidssuch as hydrochloric acid, sulfuric acid, nitric acid, etc.; and organicacids such as trifluoroacetic acid, trichloroacetic acid, acetic acid,methanesulfonic acid, p-toluenesulfonic acid, etc. can be mentioned,with preference given to hydrochloric acid.

The reaction temperature is generally −30° C. to 60° C., preferably 0°C. to room temperature.

The reaction time is generally 1 hr to 24 hr, preferably 2 hr to 12 hr.

The obtained compound (3) can be used in the next reaction withoutisolation.

Step A-2

General sulfonylation is performed. A compound of the formula (3) isreacted with a compound of the formula (4) in a solvent in the presenceof a base to give a compound of the formula (1-a), which is one of theobjective compounds.

As the base to be used for the reaction is, for example, alkali metalhydrides such as sodium hydride, potassium hydride, etc.; alkali metalcarbonates such as sodium carbonate, potassium carbonate, cesiumcarbonate, sodium hydrogen carbonate, potassium hydrogen carbonate,etc.; alkali metal carboxylates such as sodium acetate, potassiumacetate, etc.; alkali metal phosphate such as sodium phosphate,potassium phosphate, etc.; organic bases such as triethylamine,diisopropylethylamine, pyridine, N-methylmorpholine,N,N-dimethylaminopyridine, etc. can be mentioned, with preference givento triethylamine and N,N-dimethylaminopyridine.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, water, etc.; etc. can be mentioned,which may be used alone or in combination. A preferable solvent in thisreaction is a mixed solvent of dioxane and water.

The reaction temperature is generally −30° C. to 60° C., preferably 0°C. to room temperature.

The reaction time is generally 2 hr to 24 hr, preferably 4 hr to 12 hr.

Step A-3

General amidation is performed. A compound of the formula (1-a) isreacted with a hydroxyamine derivative using a condensing agent in asolvent in the presence of a base to give a compound of the formula(1-b), which is one of the objective compounds.

As the base to be used for the reaction, for example, alkali metalcarbonates such as sodium carbonate, potassium carbonate, cesiumcarbonate, sodium hydrogen carbonate, potassium hydrogen carbonate,etc.; alkali metal carboxylates such as sodium acetate, potassiumacetate, etc.; alkali metal phosphates such as sodium phosphate,potassium phosphate, etc.; and organic bases such as triethylamine,diisopropylethylamine, pyridine, N-methylmorpholine, etc. can bementioned, with preference given to N-methylmorpholine.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; and polar solvents such asacetone, N,N-dimethylformamide, acetonitrile, etc.; etc. can bementioned, which may be used alone or in combination. Preferablesolvents in this reaction are tetrahydrofuran and N,N-dimethylformamide.

As the condensing agent, any condensing agent used for general peptidecondensation method (e.g., acid chloride method, mixed acid anhydridemethod, etc.) can be used, with preference given to a combination ofethyl chlorocarbonate and N-methylmorpholine.

As the hydroxyamine derivative to be used for the reaction, for example,O-(trimethylsilyl)hydroxylamine, etc. can be mentioned.

The reaction temperature is generally 0° C. to 100° C., preferably roomtemperature to 60° C.

The reaction time is generally 1 hr to 24 hr, preferably 2 hr to 12 hr.

Production Method 2

wherein as R²′, the same substituents as for R² can be mentioned;

as R³′, the same substituents as for R³ can be mentioned;

R⁴⁰ is an amino group or a hydroxy group;

R⁶⁰ is —OR⁹, —NHOR⁹, —NH—SO₂—R⁹, —NHR⁹ or —R⁹, wherein R⁹ is as definedabove (provided that when R⁶⁰ is —OR⁹, then R⁹ should not be a hydrogenatom);

U′, X′ and Y′ are the same or different and each is an optionallysubstituted C₃₋₁₄ hydrocarbon ring group or an optionally substitutedheterocyclic group;

T₁, T₂, T₃, T₄, T₅, T₆, T₇, T₈, T₉, T₁₀, T₁₁, T₁₂, V′ and W′ aresubstituents to be used for subsequent conversion of functional groupand, for example, a hydrogen atom, an alkyl group, a halogen atom, ahaloalkyl group, an amino group, a hydroxyl group, a formyl group, analkylcarbonyl group, an alkylboranyl group, an alkoxyboranyl group, ahydroxyboranyl group, a methylthio group, a benzenesulfonyloxy group, ap-toluenesulfonyloxy group, a methanesulfonyloxy group, atrifluoromethanesulfonyloxy group, a nitro group, a cyano group, analkoxycarbonyl group, an amido group, an azido group, an alkoxy group, acarboxyl group, etc. can be mentioned, and when conversion of functionalgroup is not necessary, T₁, T₂, T₃ and T₄ remain in V′ or W′ in themolecule of the compound of the claim;

P₁, P₂ and P₄ are conventional protecting groups of carboxyl group, andas the protecting group, for example, a methyl group, an ethyl group, at-butyl group, a benzyl group, a p-methoxybenzyl group, an allyl group,a t-butyldimethylsilyl group, etc. can be mentioned, wherein, dependingon the step, P₄ may be a hydrogen atom;

P₃ is a conventional protecting group of amino group, and as theprotecting group, a t-butoxycarbonyl group, a benzyloxycarbonyl group, a9-fluorenylmethoxycarbonyl group, etc. can be mentioned, wherein,depending on the step, P₃ may be a hydrogen atom;

P₅ is an alkyl type protecting group of nitrogen atom, and an allylgroup, a trichloroethyl group, a trimethylsilylethyl group, a benzylgroup and a p-methoxybenzyl group can be mentioned, wherein, dependingon the step, P₅ may be a hydrogen atom;

P₆ is a conventional protecting group of a hydroxyl group, and as theprotecting group, for example, ethers such as a tetrahydropyranyl group,a benzyl group, a methoxymethyl group, a benzyloxymethyl group, atrimethylsilylethyloxymethyl group, etc.; esters such as a pivaloylgroup, an acetyl group, a benzoyl group, etc.; silyl ether protectinggroups such as a trimethylsilyl group, a t-butyldimethylsilyl group, at-butyldiphenylsilyl group, etc.; etc. can be mentioned, wherein,depending on the step, P₆ may be a hydrogen atom.

Step 1-1

In this Step, the epoxide of the formula 10 is reacted with MeSH in thepresence of a base to give an alcohol of the formula 11. For thereaction, a base is used, but an alkali metal salt of MeSH such assodium thiomethoxide can be also used.

As the base, for example, alkyl lithiums such as butyl lithium, t-butyllithium, s-butyl lithium, etc.; alkali metal hydrides such as sodiumhydride, potassium hydride, etc.; metal alcoholates such as potassiumt-butoxide, sodium ethoxide, sodium methoxide, etc.; alkali metal amidessuch as lithium diisopropylamide, sodium bis(trimethylsilyl)amide,lithium bis(trimethylsilyl)amide, etc.; alkali metal carbonates such assodium carbonate, potassium carbonate, sodium hydrogen carbonate,potassium hydrogen carbonate, etc.; alkali metal hydroxides such aslithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; alkalimetal carboxylate such as sodium acetate, potassium acetate, etc.;alkali metal phosphates such as sodium phosphates, potassium phosphates,etc.; organic bases such as triethylamine, pyridine, N-methylmorpholine,2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.; etc. can bementioned, with preference given to alkali metal hydroxide.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; alcohol solvents such asmethanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc.; estersolvents such as ethyl acetate, methyl acetate, butyl acetate, etc.;polar solvents such as acetone, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, water, etc.; etc. can be mentioned, which maybe used alone or in combination. A preferable solvent in this reactionis alcohol solvent, and a mixed solvent of methanol and water is morepreferable.

The reaction temperature is generally 0° C. to 100° C., preferably roomtemperature to 80° C.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 12 hr.

Thus obtained compound of the formula II can be used in the nextreaction without isolation.

Step 1-2

In this Step, the alcohol of the formula II obtained in Step 1-1 isconverted to a halide or sulfonate of the formula 12.

Either T₁₀ or T₁₁ of compound 12 obtained by this Step is a methylthiogroup (MeS group), and one of T₁₀ and T₁₁ is a leaving groups such asCl, Br, I, OMs, OTs, OSO₂Ph, OTf, etc. Depending on the substituentsR^(2′), R^(3′), R²⁰, R²¹, T₁ and T₂, compound 12 becomes a mixture ofisomers. For example, when the alcohol of the formula II is convertedinto a compound of formula 12 wherein one of T₁ and T₁₀ is Cl, thereagent to be used for this Step includes thionyl chloride, phosphorousoxychloride, phosphorus pentachloride, hydrogen chloride and the like,with preference given to thionyl chloride. In this case, the reactioncan be also carried out in the presence of a base.

As the base, organic bases such as triethylamine, pyridine,N-methylmorpholine, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene,etc.; etc. can be mentioned, with preference given to pyridine.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, acetonitrile, etc.; etc. can bementioned, which may be used alone or in combination. A preferablesolvent in this reaction is hydrocarbon solvent, and toluene is morepreferable.

The reaction temperature is generally −20° C. to 50° C., preferably 0°C. to room temperature.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 6 hr.

Thus obtained compound of the formula 12 can be used in the nextreaction without isolation.

When one of T₁₁ and T₁₀ is sulfonate, the compound can be obtained withsulfonyl chloride in the presence of a base. As the sulfonyl chloride,methanesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonylchloride; etc. can be mentioned, with preference given tomethanesulfonyl chloride. In this case, the reaction is carried out inthe presence of a base.

As the base, organic bases such as triethylamine, pyridine,N-methylmorpholine, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene,etc.; etc. can be mentioned, with preference given to pyridine.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, acetonitrile, etc.; etc. can bementioned, which may be used alone or in combination. A preferablesolvent in this reaction is hydrocarbon solvent, and toluene is morepreferable.

The reaction temperature is generally −20° C. to 50° C., preferably 0°C. to room temperature.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 6 hr.

Thus obtained compound of the formula 12 can be used in the nextreaction without isolation.

Step 1-3

In this Step, the alkene of the formula 13 is reacted with sulfenylhalide based on the method known from Synthesis (1980, 9, 690-691) togive a compound of the formula 12. For example, when methanesulfenylchloride obtained from sulfuryl chloride and dimethyl disulfide is usedas a reaction reagent, one of T₁₀ and T₁₁ in the product 12 is amethylthio group (MeS group) and one of them is Cl (leaving group).Depending on the substituent R^(2′), R^(3′), R²⁰, R²¹, T₁ and T₂,compound 12 becomes a mixture of isomers.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, acetonitrile, etc.; etc. can bementioned, which may be used alone or in combination. A preferablesolvent in this reaction is ether solvent, and 1,2-dimethoxyethane ismore preferable.

The reaction temperature is generally −78° C. to 50° C., preferably −50°C. to room temperature.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 12 hr.

Thus obtained compound of the formula 12 can be used in the nextreaction without isolation.

Step 1-4

In this Step, one of T₁₀ and T₁₁, the leaving group in the compound ofthe formula 14 obtained in Step 1-2 or 1-3 is substituted by a malonicacid diester based on the method known from Synthesis (1980, 9, 690-691)to give the halide of the formula 12). The reaction is carried out inthe presence of a base.

As the base, for example, alkyl lithiums such as butyl lithium, t-butyllithium, s-butyl lithium, etc.; alkali metal hydrides such as sodiumhydride, potassium hydride, etc.; metal alcoholates such as potassiumt-butoxide, sodium-butoxide, sodium ethoxide, sodium methoxide, etc.;alkali metal amides such as lithium diisopropylamide, sodiumbis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, etc.; alkalimetal carbonates such as sodium carbonate, potassium carbonate, sodiumhydrogen carbonate, potassium hydrogen carbonate, etc.; organic basessuch as triethylamine, pyridine, N-methylmorpholine, 2,6-lutidine,1,8-diazabicyclo[5.4.0]undec-7-ene, etc.; etc. can be mentioned. Apreferable base is metal alcoholate, and when, for example, P₁ and P₂are each ethyl, sodium ethoxide is preferable.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;alcohol solvents such as methanol, ethanol, isopropyl alcohol, t-butylalcohol, etc.; polar solvents such as N,N-dimethylformamide, dimethylsulfoxides such as, etc.; etc. can be mentioned, which may be used aloneor in combination. A preferable solvent in this reaction is alcoholsolvent, and when, for example, P₁ and P₂ are each an ethyl group,ethanol is more preferable.

The reaction temperature is generally −50° C. to 100° C., preferably 0°C. to room temperature to 50° C.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 12 hr.

Thus obtained compound of the formula 14 can be used in the nextreaction without isolation.

Step 1-5

In this Step, divalent sulfur in the compound of the formula 14 obtainedin Step 1-4 is alkylated by a conventional method based on the methodknown from Synthesis (1980, 9, 690-691) to give a sulfonium salt of theformula 15). As the reagent for the sulfonium salt formation, methyliodide, methyl p-toluenesulfonate, methyl trifluoromethanesulfonate,dimethyl sulfate; etc. can be mentioned, with preference given todimethyl sulfate or methyl p-toluenesulfonate.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; alcohol solvents such asmethanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc.; estersolvents such as ethyl acetate, methyl acetate, butyl acetate, etc.;polar solvents such as acetone, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, water, etc.; etc. can be mentioned, which maybe used alone or in combination. A preferable solvent in this reactionis hydrocarbon solvent, and no solvent is more preferable.

The reaction temperature is generally 0° C. to 150° C., preferably 50°C. to 120° C.

The reaction time is 1 hr to 48 hr, preferably 6 hr to 18 hr.

Thus obtained compound of the formula 15 can be used in the nextreaction without isolation.

Step 1-6

In this Step, the compound of the formula 15 obtained in Step 1-5 istreated with a base to form a cyclopropane skeleton based on the methodknown from Synthesis (1980, 9, 690-691), thereby affording a compound ofthe formula 16.

As the base, for example, alkyl lithiums such as butyl lithium, t-butyllithium, s-butyl lithium, etc.; alkali metal hydrides such as sodiumhydride, potassium hydride, etc.; metal alcoholates such as potassiumt-butoxide, sodium ethoxide, sodium methoxide, etc.; alkali metal amidessuch as lithium diisopropylamide, sodium bis(trimethylsilyl)amide,lithium bis(trimethylsilyl)amide, etc.; alkali metal carbonates such assodium carbonate, potassium carbonate, sodium hydrogen carbonate,potassium hydrogen carbonate, etc.; alkali metal hydroxides such aslithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; alkalimetal carboxylates such as sodium acetate, potassium acetate, etc.;organic bases such as triethylamine, pyridine, N-methylmorpholine,2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.; etc. can bementioned. A preferable base is metal alcoholate and when, for example,P₁ and P₂ are both an ethyl group, sodium ethoxide is more preferable.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;alcohol solvents such as methanol, ethanol, isopropyl alcohol, t-butylalcohol, etc.; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, etc.; etc. can be mentioned, which may be usedalone or in combination. A solvent preferable for this reaction arealcohol solvents and when, for example, P₁ and P₂ are each an ethylgroup, ethanol is more preferable.

The reaction temperature is generally −30° C. to 100° C., preferably 0°C. to 80° C.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 12 hr.

Thus obtained compound of the formula 16 can be used in the nextreaction without isolation.

Step 1-7

In this Step, the alkene of the formula 13 is reacted with bromomalonicacid diester in the presence of a catalyst and a base based on themethod known from Bull. Chem. Soc. Jpn. (2, 55, 2687-2688) to give acompound of the formula 16.

As the catalyst, copper chloride, copper bromide, copper iodide, etc.can be used, with preference given to copper (II) bromide. As the base,for example, alkyl lithium such as butyl lithium, t-butyl lithium,s-butyl lithium, etc.; alkali metal hydrides such as sodium hydride,potassium hydride, etc.; metal alcoholates such as potassium t-butoxide,sodium ethoxide, sodium methoxide, etc.; alkali metal amides such aslithium diisopropylamide, sodium bis(trimethylsilyl)amide, lithiumbis(trimethylsilyl)amide, etc.; alkali metal carbonates such as sodiumcarbonate, potassium carbonate, sodium hydrogen carbonate, potassiumhydrogen carbonate, etc.; alkali metal hydroxides such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, etc.; alkali metalcarboxylates such as sodium acetate, potassium acetate, etc.; alkalimetal phosphate such as sodium phosphate, potassium phosphate, etc.;organic bases such as triethylamine, pyridine, N-methylmorpholine,2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.; etc. can bementioned. A preferable base is organic base, and1,8-diazabicyclo[5.4.0]undec-7-ene is more preferable.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; alcohol solvents such asmethanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc.; estersolvents such as ethyl acetate, methyl acetate, butyl acetate, etc.;polar solvents such as acetone, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, water, etc.; etc. can be mentioned, which maybe used alone or in combination. A preferable solvent in this reactionis hydrocarbon solvent, and toluene is more preferable.

The reaction temperature is generally −20° C. to 100° C., preferably 0°C. to room temperature.

The reaction time is 1 hr to 48 hr, preferably 6 hr to 24 hr.

Thus obtained compound of the formula 16 can be used in the nextreaction without isolation.

This Step can be also achieved by a conventional method usingdiazomalonic acid diester or the method known from Synlett (2001, 12,1843-1846). In the latter case, for example, a compound of the formula16 can be also obtained by reacting the alkene of the formula 13 withbis(methoxycarbonyl)(phenyliodono)methanide in the presence of acatalyst.

As the catalyst, rhodium complexes and copper complexes can be used,with preference given to rhodium (II) acetate dimer.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; alcohol solvents such asmethanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc.; estersolvents such as ethyl acetate, methyl acetate, butyl acetate, etc.;polar solvents such as acetone, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, water, etc.; etc. can be mentioned, which maybe used alone or in combination. A preferable solvent in this reactionis halogenated solvent, and no solvent is more preferable.

The reaction temperature is generally room temperature to 180° C.,preferably 80° C. to 150° C.

The reaction time is 10 min to 48 hr, preferably 10 min to 6 hr.

Thus obtained compound of the formula 16 can be used in the nextreaction without isolation.

Step 1-8

In this Step, the cyclic sulfonate of the formula 17 is reacted withmalonic acid diester based on the method known from Chirality (2000, 12,551-557) to give a compound of the formula 16.

The reaction is carried out in the presence of a base, and as the base,for example, alkyl lithiums such as butyl lithium, t-butyl lithium,s-butyl lithium, etc.; alkali metal hydride such as sodium hydride,potassium hydride, etc.; metal alcoholates such as potassium t-butoxide,sodium ethoxide, sodium methoxide, etc.; alkali metal amides such aslithium diisopropylamide, sodium bis(trimethylsilyl)amide, lithiumbis(trimethylsilyl)amide, etc.; etc. can be mentioned. A preferable baseis alkali metal hydride, and sodium hydride is more preferable.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;alcohol solvents such as methanol, ethanol, isopropyl alcohol, t-butylalcohol, etc.; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, etc.; etc. can be mentioned, which may be usedalone or in combination. A preferable solvent in this reaction is ethersolvent, and 1,2-dimethoxyethane is more preferable.

The reaction temperature is generally 0° C. to 100° C., preferably roomtemperature to 50° C.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 12 hr.

Thus obtained compound of the formula 16 can be used in the nextreaction without isolation.

Step 1-9

In this Step, the malonic acid diester of the formula 19, which has adouble bond in a molecule, is cyclized to afford a compound of theformula 16 based on the method known from J. Org. Chem. (2002, 67,4062-4075). That is, this Step is a two-step reaction comprisingtreating compound 19 with sulfonyl azide in the presence of a base intoa diazomalonate derivative, which is then treated with a transitionmetal catalyst in the coexistence of a ligand to give compound 16.

As the base to be used for the first step, for example, alkyl lithiumssuch as butyl lithium, t-butyl lithium, s-butyl lithium, etc.; alkalimetal hydrides such as sodium hydride, potassium hydride, etc.; metalalcoholates such as potassium t-butoxide, sodium ethoxide, sodiummethoxide, etc.; alkali metal amides such as lithium diisopropylamide,sodium hexamethyl disilazide, lithium hexamethyl disilazide, etc.;alkali metal carbonates such as sodium carbonate, potassium carbonate,sodium hydrogencarbonate, potassium hydrogen carbonate, etc.; etc. canbe mentioned, with preference given to potassium carbonate.

As the sulfonyl azide, benzenesulfonyl azide, p-toluenesulfonyl azide,p-acetylaminobenzenesulfonyl azide; etc. can be mentioned, withpreference given to p-toluenesulfonyl azide.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide,acetonitrile, etc.; etc. can be mentioned, which may be used alone or incombination. A preferable solvent in this reaction is polar solvent, andacetonitrile is more preferable.

The reaction temperature is generally −20° C. to 100° C., preferably 0°C. to 50° C.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 24 hr.

Thus obtained diazomalonate can be used in the next reaction withoutisolation.

As the transition metal catalyst to be used in the subsequentcyclization reaction, rhodium complexes and copper complexes can beused, with preference given to copper (I) iodide. As the ligand to beused simultaneously, trimethyl phosphite, triethyl phosphite andtriphenyl phosphite can be mentioned, with preference given to triethylphosphite.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; and polar solvents such asacetone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.;can be mentioned, which may be used alone or in combination. Apreferable solvent in this reaction is toluene.

The reaction temperature is generally room temperature to 150° C.,preferably 50° C. to 130° C.

The reaction time is 1 hr to 48 hr, preferably 2 hr to 12 hr.

Thus obtained compound of the formula 16 can be used in the nextreaction without isolation.

Step 1-10

In this Step, the alkylidenemalonic acid diester of the formula 18 isreacted with sulfonium methylide based on the method known from J. Med.Chem. (1992, 35, 1410-1417) to give a compound of the formula 16.Sulfonium methylide is produced by treating trimethylsulfoxonium ortrimethylsulfonium halide with a base.

As the base, for example, alkyl lithiums such as butyl lithium, t-butyllithium, s-butyl lithium, etc.; alkali metal hydrides such as sodiumhydride, potassium hydride, etc.; metal alcoholates such as potassiumt-butoxide, sodium ethoxide, sodium methoxide, etc.; alkali metal amidessuch as lithium diisopropylamide, sodium bis(trimethylsilyl)amide,lithium bis(trimethylsilyl)amide, etc.; etc. can be mentioned. Apreferable base is alkali metal hydride, and sodium hydride is morepreferable.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, etc.;etc. can be mentioned, which may be used alone or in combination. Apreferable solvent in this reaction is polar solvent, and dimethylsulfoxide is more preferable.

The reaction temperature is generally −78° C. to 100° C., preferably 0°C. to 60° C.

The reaction time is 30 min to 48 hr, preferably 1 hr to 12 hr.

Thus obtained compound of the formula 16 can be used in the nextreaction without isolation.

Step 1-11

In this Step, one of the esters of cyclopropane dicarboxylic aciddiester of the formula 16 obtained in Step 1-6, 1-7-, 1-8, 1-9 or 1-10is selectively hydrolyzed to give a monoester of the formula 20. Whilethe selectivity varies depending on R^(2′), R^(3′), R²⁰, R²¹, T₁ and T₂,one of the two esters of less hindered or of being assisted byneighboring functional groups is preferentially hydrolyzed.

While the hydrolysis conditions vary depending on the kind of P₁ and P₂,when, for example, P₂ is a methyl group, the base includes, for example,alkali metal carbonates such as sodium carbonate, potassium carbonate,etc.; and alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, etc.; etc., with preference given tosodium hydroxide.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;alcohol solvents such as methanol, ethanol, isopropyl alcohol, t-butylalcohol, etc.; polar solvents such as water, etc.; etc. can bementioned, which may be used alone or in combination. A preferablesolvent in this reaction is alcohol solvent, and a mixed solvent ofethanol or methanol and water is more preferable.

The reaction temperature is generally 0° C. to 100° C., preferably 0° C.to room temperature.

The reaction time is 1 hr to 48 hr, preferably 6 hr to 24 hr.

Thus obtained compound of the formula 20 can be used in the nextreaction without isolation.

When P₁ and T₂ are combined and forming single bond, the compound of theformula 16 is lactone and this Step may be performed by leading thecompound to an intermediate (Weinreb amide). In this case, a CO₂P₁moiety of the resulting compound 20 is CONMe(OMe). T₂ is a hydroxylgroup derived from lactone, or a substituent derived from the hydroxylgroup such as alkyl ether, etc.

Step 1-12

In this Step, the dicarboxylic acid monoester of the formula 20 obtainedin Step 1-11 is led to a compound of the formula 21. In this Curtiusrearrangement reaction, acyl azide obtained by converting compound 20 toan activated ester by a conventional method and reacting the ester withmetal azide may be used as an intermediate. Alternatively, compound 21can also be obtained from compound 20 via acyl azide by the use ofdiphenylphosphonic azide. In addition, this Step can be applied to acompound wherein a CO₂P₁ moiety of compound 20, which is a startingmaterial, is Weinreb amide (CONMe(OMe)).

As the base, for example, organic bases such as triethylamine,diisopropylethylamine, pyridine, N-methylmorpholine, 2,6-lutidine,1,8-diazabicyclo[5.4.0]undec-7-ene etc. can be mentioned, withpreference given to triethylamine or diisopropylethylamine.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, xylene, etc.; alcoholsolvents such as benzyl alcohol, fluorenylmethyl alcohol, t-butylalcohol, etc.; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide etc.; etc. can be mentioned, which may be used alone or incombination. The solvent is appropriately chosen depending on P₃. Forexample, when P₃ is t butoxycarbonyl, t-butyl alcohol is used. Thereaction temperature is generally 0° C. to 150° C., preferably roomtemperature to 120° C.

The reaction time is 1 hr to 48 hr, preferably 6 hr to 48 hr.

Thus obtained compound of the formula 21 can be used in the nextreaction without isolation.

Step 2-1

In this Step, the alkene of the formula 22 is led to a cyclopropanederivative of the formula 23 by the method known from Synlett (2001, 12,1843-1846) or a method using diazomalonic acid diester derived frommalonic acid diester by a conventional method with a catalyst. In theformula of this Step, T₉ is a protected hydroxyl group. When, forexample, diazomalonic acid diester is used, the catalyst is preferablyrhodium complex, copper complex, etc., and rhodium (II) acetate dimer ismore preferable. As the malonic acid diester, diethyl malonate, dimethylmalonate, dibenzyl malonate, di-t-butyl malonate, etc. can be mentioned,with preference given to dimethyl malonate.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.;etc. can be mentioned, which may be used alone or in combination. Apreferable solvent in this reaction is hydrocarbon solvent, and nosolvent is more preferable.

The reaction temperature is generally room temperature to 150° C.,preferably 50° C. to 120° C.

The reaction time is 1 min to 48 hr, preferably 10 min to 3 hr.

Thus obtained compound of the formula 23 can be used in the nextreaction without isolation.

Step 2-2

In this Step, the protecting group of the substituent T₉ (protectedhydroxyl group) of the compound of the formula 23 obtained in Step 2-1is removed to give a lactone of the formula 24. The reaction conditionsare appropriately chosen depending on the kind of the protecting groupin T₉. For example, when the protecting group is t-butyldiphenylsilylgroup, deprotection is possible with an acid or fluoride.

As the acid, hydrochloric acid, sulfuric acid, phosphoric acid, aceticacid, trifluoroacetic acid, methanesulfonic acid,trifluoromethanesulfonic acid, etc. can be mentioned, with preferencegiven to trifluoroacetic acid.

As the fluoride source, hydrogen fluoride, hydrogen fluoride-pyridine,tetrabutylammonium fluoride, potassium fluoride, cesium fluoride; etc.can be mentioned, with preference given to tetrabutylammonium fluoride.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; alcohol solvents such asmethanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc.; estersolvents such as ethyl acetate, methyl acetate, butyl acetate, etc.;polar solvents such as acetone, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, water, etc.; etc. can be mentioned, which maybe used alone or in combination. A preferable solvent in this reactionis ether solvent, and THF is more preferable.

The reaction temperature is generally 0° C. to 100° C., preferably roomtemperature to 50° C.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 12 hr.

Thus obtained compound of the formula 24 can be used in the nextreaction without isolation.

Step 2-3

In this Step, the epichlorohydrin of the formula 25 is reacted withmalonic acid diester to give a lactone derivative condensed with thecyclopropane of the formula 24. R^(2′) in the compound of the formula 24obtained by this Step is methylene. The reaction is carried out in thepresence of a base. The kind of malonic acid diester is appropriatelychosen depending on PI, and dimethyl malonate, diethyl malonate,di-t-butyl malonate, dibenzyl malonate, etc. can be mentioned, withpreference given to di-t-butyl malonate.

As the base, for example, alkyl lithium such as butyl lithium, t-butyllithium, s-butyl lithium, etc.; alkali metal hydride such as sodiumhydride, potassium hydride, etc.; metal alcoholates such as potassiumt-butoxide, sodium ethoxide, sodium methoxide, etc.; alkali metal amidessuch as lithium diisopropylamide, sodium bis(trimethylsilyl)amide,lithium bis(trimethylsilyl)amide, etc.; alkali metal carbonates such assodium carbonate, potassium carbonate, sodium hydrogen carbonate,potassium hydrogen carbonate, etc.; etc. can be mentioned, withpreference given to potassium t-butoxide.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;alcohol solvents such as methanol, ethanol, isopropyl alcohol, t-butylalcohol, etc.; polar solvents such as acetone, N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile, etc.; etc. can be mentioned, which maybe used alone or in combination. A preferable solvent in this reactionis a mixed solvent of t-butyl alcohol and THF.

The reaction temperature is generally 0° C. to 150° C., preferably roomtemperature to 80° C.

The reaction time is 1 hr to 48 hr, preferably 6 hr to 24 hr.

Thus obtained compound of the formula 24 can be used in the nextreaction without isolation.

This Step can also include optical resolution process. When P₁ is at-butyl group, deprotection with an acid is performed and the obtainedracemic carboxylic acid is led to a diastereomeric salt of a chiralamine and recrystallized. The obtained chiral acid is subjected tot-butyl esterification again to give an optically active compound 24. Asthe acid to be used for deprotection under acidic conditions, mineralacids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitricacid, etc., organic acids such as trifluoroacetic acid, methanesulfonicacid, p-toluenesulfonic acid, trifluoromethanesulfonic acid and the likecan be mentioned, with preference given to hydrochloric acid ortrifluoroacetic acid.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, acetonitrile, water, etc.; etc. can bementioned. Preferable solvents in this reaction are ethyl acetate anddioxane.

The reaction temperature is generally room temperature to 100° C.,preferably room temperature to 80° C.

The reaction time is 1 hr to 48 hr, preferably 2 hr to 24 hr.

As the chiral amine to be used for optical resolution, alkaloids such ascinchonine, quinidine, cinchonidine, quinine, brucine, strychinine,etc.; amino acids or alcohols derived from amino acids such as alanine,phenylalanine, alaminol, phenylalaminol, etc.; phenethylamine,naphthylethylamine; etc. can be mentioned, with preference given toquinidine.

As the solvent to be used for recrystallization, for example, ethersolvents such as diethyl ether, tetrahydrofuran (THF), dioxane,1,2-dimethoxyethane, etc.; hydrocarbon solvents such as benzene,toluene, etc.; alcohol solvents such as methanol, ethanol, isopropylalcohol, t-butyl alcohol, etc.; ester solvents such as ethyl acetate,methyl acetate, butyl acetate, etc.; polar solvents such as acetone,2-butanone, acetonitrile, water, etc.; etc. can be mentioned, which maybe used alone or in combination. A preferable solvent in thisrecrystallization is ethanol.

For t-butyl esterification, a method using isobutene in the presence ofan acid catalyst to give t-butyl ester, or a method usingN,N-dimethylformamide di-t-butylacetal can be mentioned. For example,when N,N-dimethylformamide di-t-butylacetal is used, as the solvent, forexample, ether solvents such as diethyl ether, tetrahydrofuran (THF),dioxane, 1,2-dimethoxyethane, diglyme, etc.; hydrocarbon solvents suchas benzene, toluene, hexane, xylene, etc.; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc.; ester solvents such as ethyl acetate, methyl acetate, butylacetate, etc.; polar solvents such as acetone, N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile, etc.; etc. can be mentioned, which maybe used alone or in combination. A preferable solvent in this reactionis hydrocarbon solvent, and toluene is more preferable.

The reaction temperature is generally room temperature to 150° C.,preferably room temperature to 110° C.

The reaction time is 1 hr to 24 hr, preferably 2 hr to 12 hr.

Thus obtained compound of the formula 24 can be used in the nextreaction without isolation.

Step 2-4

In this Step, the lactone of the formula 24 obtained in Step 2-2 or 2-3is subjected to ring opening and a hydroxyl group is protected asnecessary. The reaction conditions are appropriately chosen depending onthe kind of R^(2′), R⁴⁰ and P₆. For example, when P₆ is at-butyldimethylsilyl group and R⁴⁰ is OH, this Step comprises threereactions including hydrolysis of compound 24 with alkali metalcarbonates or alkali metal hydroxides to give alkali metal carboxylate,subsequent protection of newly formed hydroxyl group and carboxyl groupwith t-butyldimethylsilyl chloride, and selective hydrolysis ofcarboxylic acid silyl ester with a base.

As the alkali metal carbonates used in the hydrolysis of lactone,potassium carbonate, sodium carbonate, etc. can be mentioned. As thealkali metal hydroxides, sodium hydroxide, potassium hydroxide; etc. canbe mentioned, with preference given to sodium hydroxide.

As the solvent used in the hydrolysis, for example, ether solvents suchas diethyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane,diglyme, etc.; alcohol solvents such as methanol, ethanol, isopropylalcohol, t-butyl alcohol, etc.; polar solvents such as water, etc.; etc.can be mentioned, which may be used alone or in combination. Apreferable solvent in this reaction is ether solvent, and a mixedsolvent of THF and water is more preferable.

The reaction temperature is generally 0° C. to 100° C., preferably roomtemperature to 80° C.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 12 hr.

The subsequent protection of the newly formed hydroxyl group with at-butyldimethylsilyl group is performed in the presence of a base. Asthe base, for example, organic bases such as triethylamine, pyridine,N-methylmorpholine, imidazol, etc.; etc. can be mentioned, withpreference given to imidazol.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.;etc. can be mentioned, which may be used alone or in combination. Apreferable solvent in this reaction is polar solvent, andN,N-dimethylformamide is more preferable.

The hydrolysis of carboxylic acid silyl ester can be performed inone-pot together with the above-mentioned reaction. That is, after thecompletion of the above-mentioned reaction, water and an alcoholsolvent, and a base are added to the reaction, whereby carboxylic acidsilyl ester can be selectively hydrolyzed.

As the alcohol solvents, methanol can be preferably used.

As the base, alkali metal carbonates such as sodium carbonate, potassiumcarbonate, sodium hydrogen carbonate, potassium hydrogen carbonate,etc.; alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, etc.; etc. can be mentioned. Apreferable base is alkali metal carbonate, and potassium carbonate ismore preferable.

The reaction temperature is generally 0° C. to 100° C., preferably 0° C.to 50° C.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 12 hr.

Thus obtained compound of the formula 26 can be used in the nextreaction without-isolation.

For example, the compound of the formula 26 wherein R⁴⁰ is a NH₂ groupand P₆ is a hydrogen atom can be obtained by treating the lactone of theformula 24 obtained in Step 2-3 with ammonia.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;alcohol solvents such as methanol, ethanol, isopropyl alcohol, t-butylalcohol, etc.; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, water, etc.; etc. can be mentioned, which maybe used alone or in combination. A preferable solvent in this reactionis a mixed solvent of methanol, water and THF.

The reaction temperature is generally 0° C. to 100° C., preferably 0° C.to 50° C.

The reaction time is 1 hr to 48 hr, preferably 6 hr to 24 hr.

Thus obtained compound of the formula 26 can be used in the nextreaction without isolation.

Step 2-5

In this Step, the compound of the formula 26 obtained in Step 2-4 is ledto a cyclic urethane of the formula 27. For example, when R⁴⁰ is OH andP₆ is a trialkylsilyl-protecting group, compound 27 can be obtained by aCurtius rearrangement reaction and subsequent deprotection of thetrialkylsilyl protecting group. That is, compound 26 is treated withdiphenylphosphonic azide in the presence of a base to give anisocyanate, which is then led to compound 27 by addition of a fluorideto the reaction to deprotect the silyl group.

As the base, organic bases such as triethylamine, pyridine,N-methylmorpholine, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene,etc.; etc. can be mentioned, with preference given to triethylamine.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, acetonitrile, water, etc.; etc. can bementioned, which may be used alone or in combination. A preferablesolvent in this reaction is polar solvent, and N,N-dimethylformamide ismore preferable.

The reaction temperature is generally room temperature to 150° C.,preferably room temperature to 80° C.

The reaction time is 10 min to 48 hr, preferably 10 min to 6 hr.

As the fluoride source, after completion of Curtius rearrangement,hydrogen fluoride, hydrogen fluoride-pyridine, tetrabutylammoniumfluoride, potassium fluoride, cesium fluoride; etc. can be mentioned,with preference given to cesium fluoride. The reaction temperature forthis reaction is generally 0° C. to 100° C., preferably room temperatureto 80° C.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 6 hr.

Thus obtained compound of the formula 27 can be used in the nextreaction without isolation.

In addition, for example, a Hofmann rearrangement reaction can be usedfor the compound of the formula 26 wherein R⁴⁰ is NH₂ and P₆ is ahydrogen atom. As the oxidizing agent to be used for the Hofmannrearrangement, N-bromosuccinimide, N-chlorosuccinimide, sulfurylchloride, bromine, iodosobenzene diacetate and the like can be used,with preference given to iodosobenzene diacetate.

The reaction may be carried out in the presence of a base, and as thebase, alkali metal carbonates such as sodium carbonate, potassiumcarbonate, sodium hydrogen carbonate, potassium hydrogen carbonate,etc.; alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, etc.; etc. can be mentioned, withpreference given to sodium hydroxide.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, acetonitrile, water, etc.; etc. can bementioned, which may be used alone or in combination. A preferablesolvent in this reaction is a mixed solvent of acetonitrile, ethylacetate and water.

The reaction temperature is generally −20° C. to 100° C., preferably 0°C. to room temperature.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 12 hr.

Thus obtained compound of the formula 27 can be used in the nextreaction without isolation.

Step 2-6

In this Step, the cyclic urethane of the formula 27 obtained in Step 2-5is subjected to ring opening reaction to give an N-protected alcohol ofthe formula 21. In the compound of the formula 21 obtained by this Step,T₂ is OH. For example, when R^(2′) is methylene and P₃ is at-butoxycarbonyl group, this Step comprises two sequential reactions.The first step is protection of a nitrogen atom of compound 27 with at-butoxycarbonyl group, and the second step is hydrolysis of cyclicurethane. In this case, as the butoxycarbonylation reagent to be used inthe first step, for example, di-t-butyl dicarbonate is used and thereaction is carried out in the presence of a base as necessary.

As the base to be used in the first step, for example, alkyl lithiumssuch as butyl lithium, t-butyl lithium, s-butyl lithium, etc.; alkalimetal hydrides such as sodium hydride, potassium hydride, etc.; alkalimetal amides such as lithium diisopropylamide, sodiumbis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, etc.; etc.can be mentioned. A preferable base is one of alkali metal hydrides, andsodium hydride is more preferable.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, etc.;etc. can be mentioned, which may be used alone or in combination. Apreferable solvent in this reaction is ether solvent, and THF is morepreferable.

The reaction temperature is generally −20° C. to 100° C., preferably 0°C. to 50° C.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 24 hr.

The second step is hydrolysis with a base.

As the base to be used in the second step, for example, alkali metalcarbonates such as sodium carbonate, potassium carbonate, cesiumcarbonate, sodium hydrogen carbonate, potassium hydrogen carbonate,etc.; alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, etc.; etc. can be mentioned, withpreference given to alkali metal carbonate, and cesium carbonate is morepreferable.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;alcohol solvents such as methanol, ethanol, isopropyl alcohol, t-butylalcohol, etc.; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, water, etc.; etc. can be mentioned, which may be used aloneor in combination. A preferable solvent in this reaction is alcoholsolvent, and methanol is more preferable.

The reaction temperature is generally 0° C. to 100° C., preferably roomtemperature to 50° C.

The reaction time is 10 min to 24 hr, preferably 30 min to 6 hr.

Thus obtained compound of the formula 21 can be used in the nextreaction without isolation.

Step 3-1

In this Step, the glycine derivative of the formula 28 is reacted withdihaloalkane or dihaloalkene in the presence of a base to give acyclopropane derivative of the formula 21. Dihaloalkane and dihaloalkeneare appropriately chosen depending on R²⁰, R²¹, R^(2′), R^(3′), T₁ andT₂

As the base, for example, alkyl lithiums such as butyl lithium, t-butyllithium, s-butyl lithium, etc.; alkali metal hydrides such as sodiumhydride, potassium hydride, etc.; metal alcoholates such as potassiumt-butoxide, sodium ethoxide, sodium methoxide, etc.; alkali metal amidessuch as lithium diisopropylamide, sodium bis(trimethylsilyl)amide,lithium bis(trimethylsilyl)amide, etc.; etc. can be mentioned, withpreference given to metal alcoholate, and potassium t-butoxide is morepreferable.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, etc.;etc. can be mentioned, which may be used alone or in combination. Apreferable solvent in this reaction is ether solvent, and THF is morepreferable.

The reaction temperature is generally −100° C. to 50° C., preferably−78° C. to room temperature.

The reaction time is 1 hr to 24 hr, preferably 1 hr to 8 hr.

Thus obtained compound of the formula 21 can be used in the nextreaction without isolation.

Step 4-1

In this Step, the alkene of the formula 13 is reacted with nitroaceticacid ester, in the presence of iodosobenzene diacetate and a catalystbased on the method known from J. Org. Chem. (2004, 69, 1262-1269), andthe compound of the formula 21 is obtained via a subsequent reductivereaction.

The catalyst to be used for the reaction is rhodium complex or coppercomplex, with preference given to a rhodium (II) pivalate dimer.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; alcohol solvents such asmethanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc.; estersolvents such as ethyl acetate, methyl acetate, butyl acetate, etc.;polar solvents such as acetone, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, water, etc.; etc. can be mentioned, which maybe used alone or in combination. A preferable solvent in this reactionis water or no solvent.

The reaction temperature is generally −20° C. to 100° C., preferablyroom temperature to 40° C.

The reaction time is 1 hr to 48 hr, preferably 2 hr to 24 hr.

As the reduction condition employed for the subsequent reaction,hydrogenation reaction in the presence of a palladium catalyst,reductive reaction using tin (II) chloride, iron, zinc and the likeunder acidic conditions reductive reaction using sodium borohydride inthe presence of copper acetate can be mentioned, with preference givento conditions using zinc in the presence of hydrochloric acid.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; alcohol solvents such asmethanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc.; estersolvents such as ethyl acetate, methyl acetate, butyl acetate, etc.;polar solvents such as acetone, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, water, etc.; etc. can be mentioned, which maybe used alone or in combination. A preferable solvent in this reactionis alcohol solvent, and isopropyl alcohol is more preferable.

The reaction temperature is generally −20° C. to 100° C., preferably 0°C. to room temperature.

The reaction time is 1 hr to 48 hr, preferably 2 hr to 12 hr.

Thus obtained compound of the formula 21 can be used in the nextreaction without isolation.

Step 5-1

In this Step, the ester of the formula 21 obtained in Step 1-12, 2-6,3-1 or 4-1 is led to a carboxylic acid of the formula 29 by aconventional method. The reaction conditions are appropriately chosendepending on P₁ and when, for example, P₁ is a methyl group or ethylgroup, hydrolysis with a conventional base can be performed. Inaddition, when, for example, P₁ is a t-butyl group, deprotection with anacid can be performed. Thus obtained racemic compound 29 can besubjected to optical resolution using a chiral amine, to give compound29 of optically active.

As a base to be used for hydrolysis under basic conditions, for example,alkali metal carbonates such as cesium carbonate, sodium carbonate,potassium carbonate, etc.; alkali metal hydroxides such as lithiumhydroxide, sodium-hydroxide, potassium hydroxide, etc.; etc. can bementioned, with preference given to sodium hydroxide. As an acid to beused for deprotection under acidic conditions, mineral acids such ashydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc.;organic acids such as trifluoroacetic acid, methanesulfonic acid,p-toluenesulfonic acid, trifluoromethanesulfonic acid, etc.; etc. can bementioned, with preference given to hydrochloric acid or trifluoroaceticacid.

As the solvent, for example, for hydrolysis under basic conditions,ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane,1,2-dimethoxyethane, diglyme, etc.; alcohol solvents such as methanol,ethanol, isopropyl alcohol, t-butyl alcohol, etc.; polar solvents suchas water, etc.; etc. can be mentioned, which may be used alone or incombination. A preferable solvent in this reaction is a mixed solvent ofether and alcohol, and a mixed solvent of methanol, THF and water ismore preferable.

The reaction temperature is generally room temperature to 100° C.,preferably room temperature to 80° C.

The reaction time is 1 hr to 48 hr, preferably 2 hr to 24 hr. Fordeprotection under acidic conditions, as the solvent, for example, ethersolvents such as diethyl ether, tetrahydrofuran (THF), dioxane,1,2-dimethoxyethane, diglyme, etc.; hydrocarbon solvents such asbenzene, toluene, hexane, xylene, etc.; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc.; ester solvents such as ethyl acetate, methyl acetate, butylacetate, etc.; polar solvents such as acetone, N,N-dimethylformamide,acetonitrile, water, etc.; etc. can be mentioned. A preferable solventis ethyl acetate, dioxane, dichloromethane, chloroform or no solvent.

Thus obtained compound of the formula 29 can be used in the nextreaction without isolation.

In addition, an optically active compound of the formula 29 can beobtained by recrystallization of diastereomeric salt of the racematewith chiral amine.

As the chiral amine, alkaloids such as cinchonine, quinidine;cinchonidine, quinine, brucine, strychinine, etc.; amino acids oralcohols derived from amino acid such as alanine, phenylalanine,alaminol, phenylalaminol, etc.; phenethylamine, naphthylethylamine; etc.can be mentioned, with preference given to quinidine.

As the solvent to be used for recrystallization, for example, ethersolvents such as diethyl ether, tetrahydrofuran (THF), dioxane,1,2-dimethoxyethane, etc.; hydrocarbon solvents such as benzene,toluene, etc.; alcohol solvents such as methanol, ethanol, isopropylalcohol, t-butyl alcohol, etc.; ester solvents such as ethyl acetate,methyl acetate, butyl acetate, etc.; polar solvents such as acetone,2-butanone, acetonitrile, water, etc.; etc. can be mentioned, which maybe used alone or in combination. A preferable solvent in thisrecrystallization is isopropyl alcohol, acetone, ethyl acetate or amixed solvent thereof.

This Step is performed as necessary or may be omitted. The compound ofthe formula 21 can be treated as the compound of the formula 30, 31 or32.

Step 5-2

In this Step, the carboxylic acid of the formula 29 obtained in Step 5-1is protected using a protecting group P₄ by a conventional method. WhileP₄ is appropriately chosen depending on P₃, T₁, or T₂, when, forexample, P₄ is a t-butyl group, a method using isobutene in the presenceof an acid catalyst or a method using N,N-dimethylformamidedi-tert-butyl acetal can be mentioned.

When, for example, N,N-dimethylformamide di-tert-butyl acetal is used,as the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.;etc. can be mentioned, which may be used alone or in combination. Apreferable solvent in this reaction is a hydrocarbon solvent, andtoluene is more preferable.

The reaction temperature is generally room temperature to 150° C.,preferably room temperature to 110° C.

The reaction time is 1 hr to 24 hr, preferably 2 hr to 12 hr.

Thus obtained compound of the formula 30 can be used in the nextreaction without isolation.

This Step is performed as necessary, or may be omitted when the nextStep and the following Steps have no problem, and the compound of theformula 29 wherein P₄ is a hydrogen atom may be used as a startingmaterial of the subsequent Steps.

Step 5-3

In this Step, substituent T₁ on R³′ and/or substituent T₂ on R²′ of thecompound of the formula 30 are/is converted to T₃ and/or T₄,respectively, under conventional conditions.

For example, when R^(3′) is an aromatic ring and T₁ is a halogen atom,so-called Negishi reaction, Suzuki-Miyaura reaction (Metal-catalyzedCross Coupling Reactions; WILEY-VCH; New York, 1998), Buchwald reaction,Ullmann reaction (Tetrahedron 2002, 11, 2041-2075; J. Am. Chem. Soc.2003, 125, 6653-6655) and the like can be applied, whereby a compound ofthe formula 31 wherein T₃ is alkoxycarbonyl alkyl, carbonylamino group,alkoxycarbonyl group, aryl group, arylamino group, alkylamino group oraryl alkoxy group can be obtained respectively.

When, for example, R^(2′) is an alkyl chain and T₂ is a hydroxyl group,for example, a compound of the formula 31 wherein T₄ is an amino groupor alkylamino group can be obtained by a conventional method. Thusobtained compound of the formula 31 can be used in the next reactionwithout isolation.

When T₁ and T₂ are hydrogen atoms or when further conversion is notnecessary, this Step is omitted and the compound of the formula 30 canbe treated as a compound of the formula 31.

Step 5-4

In this Step, P₃, which is a nitrogen-protecting group in the compoundof the formula 31, is deprotected by a conventional method. When Step(s)5-1, 5-2 and/or 5-3 are/is omitted, this Step is also a step fordeprotecting P₃ of the compounds of the formulas 21, 29 or 30. Inaddition, this Step can be applied to compound 31, wherein a CO₂P₄moiety is Weinreb amide (CONMe(OMe)). The reaction conditions areappropriately chosen depending on P₃ or P₄, when, for example, P₃ is at-butoxycarbonyl group and P₄ is a t-butyl group, deprotection can beperformed under acidic conditions.

As the acid, mineral acids such as hydrochloric acid, sulfuric acid,phosphoric acid, etc.; organic acids such as acetic acid,trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.can be mentioned, with preference given to p-toluenesulfonic acid.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; alcohol solvents such asmethanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc.; estersolvents such as ethyl acetate, methyl acetate, butyl acetate, etc.;polar solvents such as acetone, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, water, etc.; etc. can be mentioned, which maybe used alone or in combination. A preferable solvent in this reactionis ether solvent, alcohol solvent or acetonitrile.

The reaction temperature is generally 0° C. to 100° C., preferably roomtemperature to 50° C.

The reaction time is 1 hr to 72 hr, preferably 6 hr to 48 hr.

Thus obtained compound of the formula 32 can be used in the nextreaction without isolation.

When P₃ is a hydrogen atom, this Step is not necessary, and the compoundof the formula 31 can be treated as a compound of the formula 32.

Step 5-5

In this Step, the compound of the formula 32 obtained in Step 5-4 is ledto a sulfonamide or sulfamide of the formula 33. T₅ in the compound ofthe formula 33 obtained in this Step is a substituent, which is furtherled to other functional group in the next Step 5-6, 5-13 or 6-7.

When the compound of the formula 33 is a sulfonamide derivative, thecompound 33 can be obtained by a conventional reaction of the compoundof the formula 32 with ClSO₂—(CH₂)_(m)—U-T₅ or O(SO₂—(CH₂)_(m)—U-T₅)₂ inthe presence of a base, for example.

As the base, organic bases such as triethylamine, pyridine,N-methylmorpholine, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene,etc.; etc. can be mentioned, with preference given to pyridine or2,6-lutidine. These may be used as solvents.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asN,N-dimethylformamide, acetonitrile, etc.; etc. can be mentioned, whichmay be used alone or in combination. A preferable solvent in thisreaction is halogenated solvent or ether solvent, and chloroform or THFis more preferable.

The reaction temperature is generally 0° C. to 100° C., preferably roomtemperature to 50° C.

The reaction time is 1 hr to 72 hr, preferably 1 hr to 48 hr.

When the compound of the formula 33 is a sulfamide derivative, based onthe method known in Tetrahedron (1996, 52, 14217-14227), the derivativecan be synthesized by two consecutive reactions. The first step is areaction of 2-haloethanol with chlorosulfonyl isocyanate and then withthe compound of the formula 32 in the presence of a base, to give anoxazolidin-2-one-3-ylsulfamide, and the second step is a reaction of thecompound obtained above with a desired amine to give a sulfamide of theformula 33.

As the 2-haloethanol, for example, 2-chloroethanol, 2-bromoethanol and2-iodoethanol can be mentioned, with preference given to2-chloroethanol.

As the base, for example, organic bases such as triethylamine, pyridine,N-methylmorpholine, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene,etc.; etc. can be mentioned. A preferable base is organic base, andN-methylmorpholine is more preferable.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, acetonitrile, etc.; etc. can be mentioned, which may be usedalone or in combination. A preferable solvent in this reaction is polarsolvent, and acetonitrile is more preferable.

The reaction temperature is generally −20° C. to 100° C., preferably 0°C. to 50° C.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 24 hr.

The second step is a nucleophilic substitution reaction with amine.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF) dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.;etc. can be mentioned, which may be used alone or in combination. Apreferable solvent in this reaction is polar solvent, and acetonitrileis more preferable.

The reaction temperature is generally −20° C. to 100° C., preferably 0°C. to 100° C.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 24 hr.

Thus obtained compound of the formula 33 can be used in the nextreaction without isolation.

Step 5-6

In this Step, the compound of the formula 33 obtained in Step 5-5 isreacted with the compound of the formula 34 to give a compound of theformula 35. T₇ in the compound of the formula 35 obtained in this Stepis a substituent that can be led to the other substituents in Step 5-9,5-14 or 6-10. In addition, U′ in the compound of the formula 33 changesstructure by reacting with the compound of the formula 34, therebyforming a new ring X′, or may remain the structure (U′═X′).

As for one of the examples of structural change of U′ with thisreaction, can be mentioned the case, in which U′-T₅ is2-aminothiazol-4-yl and the compound of the formula 34 is anα′-haloacetone possessing T₇ at the α-position. In this case, U′-T₅structurally changes to an imidazo[2,1-b]thiazol-2-yl group possessingCH₂T₇ at the 6-position. As the solvent in this case, for example, ethersolvents such as diethyl ether, tetrahydrofuran (THF), dioxane,1,2-dimethoxyethane, diglyme, etc.; hydrocarbon solvents such asbenzene, toluene, hexane, xylene, etc.; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc.; alcohol solvents such as methanol, ethanol, isopropyl alcohol,t-butyl alcohol, etc.; ester solvents such as ethyl acetate, methylacetate, butyl acetate, etc.; polar solvents such as acetone,N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, water, etc.;etc. can be mentioned, which may be used alone or in combination. Apreferable solvent in this reaction is ester solvent, and ethyl acetateis more preferable.

The reaction temperature is generally 0° C. to 100° C., preferably roomtemperature to 80° C.

The reaction time is 1 hr to 48 hr, preferably 6 hr to 24 hr.

Thus obtained compound of the formula 35 can be used in the nextreaction without isolation.

Step 5-7

In this Step, the compound of the formula 32 obtained in Step 5-4 isdirectly led to the compound of the formula 35 without going through thecompound of the formula 33. T₇ in the compound of the formula 35obtained in this Step is a substituent that can be converted to theother substituent in Step 5-9, 5-14 or 6-10. when the compound of theformula 35 is a sulfonamide derivative, for example,ClSO₂—(CH₂)_(m)—X′—(CH₂)_(n)—Y′-T₇ orO(SO₂—(CH₂)_(m)—X′—(CH₂)_(n)—Y′-T₇)₂ is reacted with the compound of theformula 32, and when the compound of the formula 35 is a sulfamidederivative, for example, the compound can be obtained from the compoundof the formula 32 by a method similar to that of Step 5-5. Thus obtainedcompound of the formula 35 can be used in the next reaction withoutisolation.

Step 5-8

In this Step, the carboxyl group-protecting group of the compound of theformula 35 obtained in Step 5-6 or 5-7 is deprotected by a conventionalmethod. T₇ in the compound of the formula 36 obtained in this Step is asubstituent that can be converted to the other substituent in Step 5-9.The reaction conditions are similar to those in Step 5-1.

Thus obtained compound of the formula 36 can be used in the nextreaction without isolation.

Step 5-9

In this Step, T₇ in the compound of the formula 36 obtained in Step 5-8is modified by a conventional method to give a compound of the formula37. By this Step, a (CH₂)_(m)—X′—(CH₂)_(n)—Y′-T₇ moiety in the compoundof the formula 36 is converted to R¹ of the compound of the formula 37.In this Step, T₃ and T₄ do not change and correspond to V′ and W′,respectively. The reaction conditions are appropriately chosen dependingon the kind of T₇ and desired compound, when, for example, T₇ is aprotecting group of an amino group involved in Y′, this can bedeprotected by a conventional method and the amino group can be led toamide, urethane, urea, alkylamine by a conventional method. When, forexample, Y′ is an aromatic ring and T₇ is a halogen atom, T₇ on Y′ canbe led to other substituents by methods known in literature, such asso-called Sonogashira reaction, Heck reaction, Negishi reaction,Suzuki-Miyaura reaction (Metal-catalyzed Cross Coupling Reactions;WILEY-VCH; New York, 1998), Buchwald reaction, Ullmann reaction(Tetrahedron 2002, 11, 2041-2075; J. Am. Chem. Soc. 2003, 125,6653-6655) and the like. It can be led to alkyne by the Sonogashirareaction, to alkene by Heck reaction, to an aromatic ring bySuzuki-Miyaura reaction, to amine by Buchwald reaction, and to ether byUllmann reaction.

Step 5-10.

In this Step, a hydrogen atom of the compound of the formula 46 isreplaced with a chlorosulfonyl group. After leading the compound of theformula 46 to a sulfonic acid derivative, the derivative is subsequentlychlorinated to give the sulfonyl chloride derivative of the formula 47.As the sulfonylation agent, sulfuric acid, chlorosulfonic acid andchlorosulfonic acid trimethylsilyl ester can be mentioned. As thesolvent, no solvent, or halogenated solvents such as dichloromethane,chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.; estersolvents such as ethyl acetate, methyl acetate, butyl acetate, etc.;polar solvents such as acetic acid, sulfuric acid, etc.; etc. can bementioned, which may be used alone or in combination. A preferablesolvent in this reaction is halogenated solvent, and chloroform is morepreferable.

The reaction temperature is generally −20° C. to 100° C., preferably 0°C. to 50° C.

The reaction time is 1 hr to 72 hr, preferably 1 hr to 48 hr.

The subsequent chlorination reaction is a conventional synthetic methodfor a sulfonyl chloride derivative, and as the chlorinating agent to beused for the reaction, for example, thionyl chloride, phosphorousoxychloride, phosphorus pentachloride and chlorosulfonic acid can bementioned, with preference given to thionyl chloride. As the solvent, nosolvent, or hydrocarbon solvents such as benzene, toluene, hexane,xylene, etc.; halogenated solvents such as dichloromethane, chloroform,carbon tetrachloride, 1,2-dichloroethane, etc.; ester solvents such asethyl acetate, methyl acetate, butyl acetate, etc.; polar solvents suchas acetone, N,N-dimethylformamide, etc.; etc. can be mentioned, whichmay be used alone or in combination. A preferable solvent in thisreaction is no solvent, and a mixed solvent of thionyl chloride, whichis a chlorinating agent, and a catalytic amount of N,N-dimethylformamideis more preferable.

The reaction temperature is generally 0° C. to 100° C., preferably roomtemperature to 80° C.

The reaction time is 1 hr to 48 hr, preferably 3 hr to 24 hr.

Thus obtained compound of the formula 47 can be used in the nextreaction without isolation.

Step 5-11

In this Step, the amine of the formula 32 obtained in Step 5-4 is led toa sulfonamide derivative or sulfamide derivative of the formula 48. Inaddition, this Step can be also applied to a compound 32, wherein aCO₂P₄ moiety is Weinreb amide (CONMe(OMe)). When the compound of theformula 48 is a sulfonamide derivative, for example, the derivative canbe obtained by a reaction with the ClSO₂—R¹ of the formula 47 obtainedin Step 5-10, or O(SO₂—R¹)₂. The reaction conditions are the same asthose in Step 5-5. When the compound of the formula 48 is a sulfamidederivative, the same procedure as in Step 5-5 can be applied.

Thus obtained compound of the formula 48 can be used in the nextreaction without isolation.

Step 5-12

In this Step, the carboxyl-protecting group in the compound of theformula 48 obtained in Step 5-11 is deprotected and T₄ in compound 48 isconverted to W′ to give the compound of the formula 37.

P₄ is deprotected and T₄ is led to the other substituent simultaneouslyunder the same conditions. In addition, P₄ and T₄ may be combinedtogether to form a single bond, and when compound 48 is lactone, thisStep can be also achieved by hydrolyzing the lactone tohydroxycarboxylic acid. In this case, the reaction is carried out by abase. As the base, alkali metal carbonates such as sodium carbonate,potassium carbonate, sodium hydrogen carbonate, potassium hydrogencarbonate, etc.; alkali metal hydroxides such as lithium hydroxide,sodium hydroxide, potassium hydroxide, etc.; etc. can be mentioned, withpreference given to sodium hydroxide.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;alcohol solvents such as methanol, ethanol, isopropyl alcohol, t-butylalcohol, etc.; polar solvents such as water, etc.; can be mentioned,which may be used alone or in combination. A preferable solvent isalcohol solvent, and a mixed solvent of methanol and water is morepreferable.

The reaction temperature is generally 0° C. to 100° C., preferably roomtemperature to 60° C.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 12 hr.

Thus obtained compound of the formula 37 can be used in the nextreaction without isolation.

Step 5-13

In this Step, a carboxyl group of the compound of the formula 33obtained in Step 5-5 is deprotected and then T₅ is modified by aconventionally known method to give the compound of the formula 37. Bythis Step, a (CH₂)_(m)—U′-T₅ moiety in the compound of the formula 33 isconverted to R¹ in the compound of the formula 37. In this Step, asubstituent T₃ at R^(3′) and a substituent T₄ at R^(2′) are the same asV′ and W′, respectively.

The reaction conditions are appropriately chosen depending on the kindof T₅ and a desired compound. For example, reductive alkylation of aminogroup, conversion to a hydroxymethyl group by reduction ofalkoxycarbonyl group, conversion of halomethyl group to an alkoxymethylgroup by substitution by alkoxide and the like can be mentioned. When T5is a protecting group of amine included in U′, this is deprotected underconventional conditions and the amine was reacted with a desiredisocyanide to give a urea derivative 37. In this case, the conditions ofthe deprotection are the same as in Step 5-4. As the isocyanide, methylisocyanate, phenyl isocyanate and the like can be mentioned and thereaction with these is carried out in the presence of a base. As thebase, organic bases such as triethylamine, pyridine; N-methylmorpholine,2,6-lutidine, etc.; etc. can be mentioned, with preference given totriethylamine.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, acetonitrile, etc.; etc. can bementioned, which may be used alone or in combination. A preferablesolvent in this reaction is ether solvent, and THF is more preferable.

The reaction temperature is generally −20° C. to 100° C., preferably 0°C. to room temperature.

The reaction time is 1 hr to 24 hr, preferably 1 hr to 6 hr.

Thus obtained compound of the formula 37 can be used in the nextreaction without isolation.

Step 5-14

In this Step, T₇ of the compound of the formula 35 obtained in Step 5-6or 5-7 is modified by a conventionally known method and P₄, which is aprotecting group of carboxyl group, is simultaneously deprotected togive a compound of the formula 37. In this Step, a substituent T₃ atR^(3′) and a substituent T₄ at R^(2′) correspond to V′ and W′,respectively. For example, when T₇ is a nitro group and P₄ is a t-butylgroup, the compound of the formula 37 can be obtained using aconventional reducing agent of a nitro group in the presence of an acid.In this case, as a conventional reducing agent of a nitro group, forexample, tin (II) chloride, iron, zinc can be mentioned, with preferencegiven to tin (II) chloride. As the acid, hydrochloric acid, acetic acid,sulfuric acid, nitric acid, etc. can be mentioned, with preference givento hydrochloric acid.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;alcohol solvents such as methanol, ethanol, isopropyl alcohol, t-butylalcohol, etc.; polar solvents such as water, etc.; etc. can bementioned, which may be used alone or in combination. A preferablesolvent in this reaction is alcohol solvent, and ethanol is morepreferable.

The reaction temperature is generally room temperature to 150° C.,preferably room temperature to 100° C.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 12 hr.

Thus obtained compound of the formula 37 can be used in the nextreaction without isolation.

Step 5-15

In this Step, the carboxylic acid of the formula 37 obtained in Step5-9, 5-12, 5-13, 5-14 or 6-11 is led to a compound of the formula 38.For example, when R⁶⁰ is a NHOH group, carboxylic acid is converted toactivated ester or acid chloride in a solvent, and a hydroxylamine orits equivalent wherein a hydroxylamine or hydroxyl group is protected isadded to give a compound of the formula 38. This Step may be performedin the presence of a base. When a hydroxylamine equivalent wherein thehydroxyl group is protected is used, deprotection is necessary after thereaction.

As the activated ester, aryl imidazole, mixed acid anhydride,hydroxybenzotriazole ester, hydroxysuccinimide ester and the like can bementioned, which are prepared by known methods. For preparation of acylchloride, thionyl chloride, oxalyl chloride and the like are used. Thereaction temperature for preparation of the activated ester or acylchloride is generally −78° C. to 50° C., preferably −20° C. to roomtemperature.

The reaction time is 10 min to 6 hr, preferably 30 min to 6 hr. As thehydroxylamine equivalent wherein a hydroxyl group is protected,O-(trimethylsilyl)hydroxylamine, O-(benzyl)hydroxylamine; etc. can bementioned, with preference given to O-(trimethylsilyl)hydroxylamine.

The temperature of the reaction with the hydroxylamine equivalentwherein the hydroxyl group is protected is generally −78° C. to 50° C.,preferably −20° C. to room temperature.

The reaction time is 10 min to 6 hr, preferably 30 min to 6 hr.

As the base, organic bases such as triethylamine, pyridine,N-methylmorpholine, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene,etc.; etc. can be mentioned, with preference given toN-methylmorpholine.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; etc. can be mentioned,which may be used alone or in combination. A preferable solvent in thisreaction is ether solvent, and THF is more preferable.

When a compound of the formula (1) wherein R⁴ is a substituent otherthan —COR⁶⁰ is desired, such compound can be produced from a compound ofthe formula 38 or 37 by a known method.

Step 6-1

In this Step, the cyclic urethane of the formula 27 obtained in Step 2-5is sulfonylated and subsequently subjected to ring opening reaction witha nucleophilic agent to give a sulfonamide derivative of the formula 39.For example, when the nucleophilic agent is a base (hydroxide ion), T₈in the compound of the formula 39 obtained by this Step is a hydroxylgroup. When, for example, the nucleophilic agent is alkylamine, T₈ inthe compound of the formula 39 obtained by this Step is analkylcarbamoyloxy group. In this Step, moreover, the substituents T₁ atR^(3′) and P₁, a carboxylic protecting group of acid do not change andcorrespond to T₃ and P₄, respectively.

The sulfonylation agent is appropriately depending on the desired R¹,and ClSO₂—R¹ or O(SO₂—R¹)₂ is used for the reaction. The reaction iscarried out in the presence of a base, and as the base, for example,alkyl lithiums such as n-butyl lithium, t-butyl lithium, s-butyllithium, etc.; alkali metal hydrides such as sodium hydride, potassiumhydride, etc.; alkali metal amides such as lithium diisopropylamide,sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, etc.;etc. can be mentioned, with preference given to sodium hydride.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, etc.;etc. can be mentioned, which may be used alone or in combination. Apreferable solvent in this reaction is ether solvent, and a mixedsolvent of THF and 15-crown-5-ether is more preferable.

The reaction temperature is generally −20° C. to 100° C., preferably 0°C. to 50° C.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 24 hr.

When, for example, the nucleophilic agent in the subsequent ring-openingreactions is a base (hydroxyl anion), this reaction is conventionalhydrolysis in the presence of a base, and the base to be used for thereaction includes, for example, alkali metal carbonates such as sodiumcarbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogen carbonate, etc.; alkali metal hydroxidessuch as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.;etc. can be mentioned, with preference given to alkali metal hydroxide,and sodium hydroxide is more preferable.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;alcohol solvents such as methanol, ethanol, isopropyl alcohol, t-butylalcohol, etc.; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, water, etc.; etc. can be mentioned, which may be used aloneor in combination. A preferable solvent in this reaction is polarsolvent, and a mixed solvent of THF, methanol and water is morepreferable.

The reaction temperature is generally 0° C. to 100° C., preferably roomtemperature to 50° C.

The reaction time is 10 min to 48 hr, preferably 30 min to 24 hr.

Thus obtained compound of the formula 39 can be used in the nextreaction without isolation.

When the nucleophilic agent is alkylamine, for example, isopropylamine,morpholine, benzylamine, etc. can be mentioned as the alkylamine.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc. suchas, etc.; halogenated solvents such as dichloromethane, chloroform,carbon tetrachloride, 1,2-dichloroethane, etc.; polar solvents such asN,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.; etc. canbe mentioned, which may be used alone or in combination. A preferablesolvent in this reaction is ether solvent, and THF is more preferable.

The reaction temperature is generally 0° C. to 100° C., preferably roomtemperature to 80° C.

The reaction time is 1 hr to 24 hr, preferably 1 hr to 12 hr.

Thus obtained compound of the formula 39 can be used in the nextreaction without isolation.

Step 6-2

In this Step, a substituent T₈ at R^(2′) in the compound of the formula39 obtained in Step 6-1 is led to T₁₂ under conventional conditions. Forexample, when R^(2′) is an alkyl chain and T₈ is a hydroxyl group, thisstep includes protection of the hydroxyl group (T₈) with a conventionalprotecting group transforming into T₁₂.

T₁₂ is appropriately chosen according to P₄, or T₃, R¹, and when, forexample, T₁₂ is a hydroxyl group protected by tetrahydropyranyl ether, amethod using 3,4-dihydro-2H-pyran in the presence of an acid catalystcan be mentioned. In this case, as the acid, p-toluenesulfonic acid,pyridinium p-tolueneslufonate, camphorsulfonic acid, methanesulfonicacid, benzenesulfonic acid, hydrochloric acid, etc. can be mentioned.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.;etc. can be mentioned, which may be used alone or in combination. Apreferable solvent in this reaction is halogenated solvent, andchloroform is more preferable.

The reaction temperature is generally room temperature to 100° C.,preferably room temperature to 70° C.

The reaction time is 1 hr to 24 hr, preferably 2 hr to 12 hr.

Thus obtained compound of the formula 40 can be used in the nextreaction without isolation.

This Step is performed as necessary or may be omitted. In this case, thecompound of the formula 39 can be treated as a compound of the formula45.

Step 6-3

In this Step, a sulfonamide group of the compound of the formula 40obtained in Step 6-2 is protected with a protecting group P₅ by aconventional method. P₅ is appropriately chosen depending on P₄, T₃, T₁₂or R¹. When, for example, P₅ is a 2-trimethylsilylethyl group, a methodusing Mitsunobu reagents such as diethyl azodicarboxylate, etc. in thepresence of 2-trimethylsilylethyl alcohol can be mentioned. As thesolvent in this case, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.;etc. can be mentioned, which may be used alone or in combination. Apreferable solvent in this reaction is ether solvent, and THF is morepreferable.

The reaction temperature is generally room temperature to 100° C.,preferably room temperature to 50° C.

The reaction time is 1 hr to 96 hr, preferably 2 hr to 24 hr.

Thus obtained compound of the formula 41 can be used in the nextreaction without isolation.

Step 6-4

In this Step, a substituent T₁₂ at R^(2′) in the compound of the formula41 obtained in Step 6-3 is led to T₄ in a compound of the formula 42.For example, deprotection reaction of a hydroxyl group by a conventionalmethod and the like can be mentioned. In this case, T₄ is a hydroxylgroup, and as T₁₂, for example, a hydroxyl group protected bytetrahydropyranyl ether, acetoxy group, t-butoxy group, ort-butyldimethylsilyloxy group, etc. can be mentioned. The reactionconditions are appropriately chosen depending on P₄, P₅, T3, T₁₂ and R¹.For example, when P₄ is a t-butyl group, P₅ is a 2-trimethylsilylethylgroup and T₁₂ is a hydroxyl group protected with tetrahydropyranylether, the deprotection can be carried out in the presence of an acidcatalyst.

As the acid, mineral acids such as hydrochloric acid, sulfuric acid,phosphoric acid, etc.; organic acids such as acetic acid,trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.can be mentioned, with preference given to p-toluenesulfonic acid.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; alcohol solvents such asmethanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc.; estersolvents such as ethyl acetate, methyl acetate, butyl acetate, etc.;polar solvents such as acetone, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, water, etc.; etc. can be mentioned, which maybe used alone or in combination. A preferable solvent in this reactionis alcohol solvent, and methanol is more preferable.

The reaction temperature is generally 0° C. to 100° C., preferably roomtemperature to 50° C.

The reaction time is 30 min to 48 hr, preferably 1 hr to 12 hr.

Thus obtained compound of the formula 42 can be used in the nextreaction without isolation.

Step 6-5

In this Step, a substituent T₃ at R^(3′) and/or a substituent T₄ atR^(2′) of the compound of the formula 42 obtained in Step 6-4 are/isconverted to V′ and/or W′, respectively, under conventional conditions.For example, when R^(3′) is a benzene ring and T₃ is a halogen atom,so-called Negishi reaction, Suzuki-Miyaura reaction (Metal-catalyzedCross Coupling Reactions; WILEY-VCH; New York, 1998), Buchwald reaction,Ullmann reaction (Tetrahedron 2002, 11, 2041-2075; J. Am. Chem. Soc.2003, 125, 6653-6655) and the like can be applied, whereby the compoundof the formula 43, wherein V′ is an alkoxycarbonyl alkyl, an aryl group,an arylamino group or an aryl alkoxy group can be obtained. When, forexample, R^(2′) is an alkyl chain and T₄ is a hydroxyl group, forexample, the compound of the formula 43 wherein W′ is an alkoxy group oracyloxy group can be obtained by a conventional method.

Step 6-6

In this Step, the sulfonamide group of the compound of the formula 33obtained in Step 5-5 is protected with a protecting group P₅ by aconventional method. While P₅ can be appropriately chosen depending onP₄, T₃, T₄ or T₅, when, for example, P₅ is a 2-trimethylsilylethylgroup, a method using Mitsunobu reagents such as diethylazodicarboxylate, etc. in the presence of 2-trimethylsilylethyl alcoholcan be mentioned.

As the solvent in this case, for example, ether solvents such as diethylether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbon solvents such as benzene, toluene, hexane, xylene,etc.; halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; ester solvents such as ethylacetate, methyl acetate, butyl acetate, etc.; polar solvents such asacetone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.;etc. can be mentioned, which may be used alone or in combination. Apreferable solvent in this reaction is ether solvent, and THF is morepreferable.

The reaction temperature is generally room temperature to 100° C.,preferably room temperature to 50° C.

The reaction time is 1 hr to 96 hr, preferably 2 hr to 24 hr.

Thus obtained compound of the formula 44 can be used in the nextreaction without isolation.

This Step is performed as necessary, or may be omitted when the nextStep and the following Steps proceed without protection. In this case,the compound of the formula 33 may be treated as the compound of theformula 44 wherein P₅ is a hydrogen atom.

Step 6-7.

In this Step, a substituent T₅ at U′ of the compound of the formula 44obtained in Step 6-6 is led to the other substituent under conventionalconditions to give a compound of the formula 43. In this Step, asubstituent T₃ at R³′ and a substituent T₄ at R²′ do not change andcorrespond to V′ and W′, respectively.

For example, when U′ is an aromatic ring and T₅ is a halogen atom,so-called Negishi reaction, Suzuki-Miyaura reaction (Metal-catalyzedCross Coupling Reactions; WILEY-VCH; New York, 1998), Buchwald reaction,Ullmann reaction (Tetrahedron 2002, 11, 2041-2075; J. Am. Chem. Soc.2003, 125, 6653-6655) and the like can be applied, whereby a compound ofthe formula 43, wherein R¹ is a biaryl group or arylaminoaryl group canbe obtained, for example.

Step 6-8

In this Step, P₅, which is a protecting group of sulfonamide, in thecompound of the formula 43 obtained in Step 6-5 or 6-7 is deprotected-bya conventional method. The reaction conditions are appropriately chosendepending on P₄, and, for example, when P₄ is a t-butyl group and P₅ isa 2-trimethylsilylethyl group, deprotection can be performed using anacid or fluoride.

As the acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoricacid, trifluoroacetic acid, methanesulfonic acid,trifluoromethanesulfonic acid, etc. can be mentioned, with preferencegiven to trifluoroacetic acid. As the fluoride source, hydrogenfluoride, hydrogen fluoride-pyridine, tetrabutylammonium fluoride,potassium fluoride, etc. can be mentioned, with preference given totetrabutylammonium fluoride.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; alcohol solvents such asmethanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc.; estersolvents such as ethyl acetate, methyl acetate, butyl acetate, etc.;polar solvents such as acetone, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, water, etc.; etc. can be mentioned, which maybe used alone or in combination. A preferable solvent in this reactionis ether solvent, and THF is more preferable.

The reaction temperature is generally 0° C. to 120° C., preferably roomtemperature to 100° C.

The reaction time is 1 hr to 48 hr, preferably 1 hr to 12 hr.

Thus obtained compound of the formula 45 can be used in the nextreaction without isolation.

When Step 6-6 is omitted, this Step can be also omitted.

Step 6-9

In this Step, T₃ and/or T₄ of the compound of the formula 48 obtained inStep 5-11 are/is converted to V′ and/or W. The reaction conditions areappropriately chosen depending on P₄, T₃, T₄, V′ and W′ and when, forexample, R³′ and/or R²′ are/is an aromatic ring and T₃ and/or T₄ are/isa halogen atom, so-called Negishi reaction, Suzuki-Miyaura reaction(Metal-catalyzed Cross Coupling Reactions; WILEY-VCH; New York, 1998),Buchwald reaction, Ullmann reaction (Tetrahedron 2002, 11, 2041-2075; J.Am. Chem. Soc. 2003, 125, 6653-6655) and the like can be applied,whereby the compound of the formula 45, wherein V′ and/or W′ are/is analkoxycarbonyl alkyl group, a carbonylamino group, an alkoxycarbonylgroup, an aryl group, an arylamino group, an alkylamino group or an arylalkoxy group can be obtained.

In addition, when, for example, T₃ and/or T₄ are/is a nitro group, theycan be converted to an amino group under conventional reductionconditions. It is also possible to be followed by reductive alkylation.As the reduction conditions, hydrogenation reaction in the presence of apalladium catalyst, reductive reaction under acidic conditions using tin(II) chloride, iron, zinc, etc., and reductive reaction using sodiumborohydride in the presence of copper acetate can be mentioned. Apreferable reducing agent in this reaction is sodium borohydride in thepresence of copper (II) acetate.

As the solvent, for example, ether solvents such as diethyl ether,tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme, etc.;hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.;halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; alcohol solvents such asmethanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc.; polarsolvents such as N,N-dimethylformamide, acetonitrile, water, etc.; etc.can be mentioned, which may be used alone or in combination. Apreferable solvent in this reaction is alcohol solvent, and a mixedsolvent of chloroform and ethanol is more preferable.

The reaction time is 10 min to 12 hr, preferably 30 min to 6 hr.

For example, when T₃ and/or T₄ are/is an azido group, for example, thecompound can be led to compound 45 wherein V′ and/or W′ are/is analkylamino group or an amino group by a conventional method. Forexample, when W′ is an alkylamino group, this Step is achieved bysubjecting the amino group obtained via a conventional reduction step toreductive alkylation. In this case, the reducing agent for azidereduction is, for example, trialkylphosphine, with preference given totriphenyl phosphine. The subsequent reductive alkylation is performed bya conventional method.

Thus obtained compound of the formula 45 can be used in the nextreaction without isolation. This Step is performed as necessary or maybe omitted. In this case, the compound of the formula 48 can be treatedas the compound of the formula 45.

Step 6-10

In this Step, T₇ of the compound of the formula 35 obtained in Step 5-6or 5-7 is modified by a conventional method to give the compound of theformula 45. By this Step, a (CH₂)_(m)—X′—(CH₂)_(n)—Y′-T₇ moiety in thecompound of the formula 35 is converted to R¹ in the compound of theformula 45. The reaction conditions are appropriately chosen dependingon T₇ and the desired compound. For example, conversion of analkoxycarbonyl group to a hydroxymethyl group, conversion of ahalomethyl group to an alkoxymethyl group and the like can be mentioned.

Thus obtained compound of the formula 45 can be used in the nextreaction without isolation.

Step 6-11

In this Step, a protecting group of the carboxyl group in the compoundof the formula 45 obtained in Step 6-8, 6-9 or 6-10 is deprotected togive a compound of the formula 37. This Step can be also applied to acompound wherein a CO₂P₄ moiety of compound 45 is Weinreb amide(CONMe(OMe)). The reaction conditions are appropriately chosen dependingon the kind of P₄ and the same as those in Step 5-1. In addition, thisStep is performed as necessary, or omitted when P₄ is a hydrogen atom.

The production methods described in the specification are among theexamples of the production method of the compound of the presentinvention, and compounds other than those explained in the above can beproduced by combining conventional methods known in the field of organicsynthetic chemistry.

The compound represented by the formula (1) and production methodthereof of the present invention is explained in detail in the followingby way of Examples. It is needless to say that the present invention isnot limited by these Examples.

PREPARATION EXAMPLE 1-1 (2R*,3R*)-3-methylsulfanyl-2-phenyl-butan-2-ol(Step 1-1)

To a solution of trans-2,3-dimethyl-2-phenyloxirane (14 g, 76 mmol) inmethanol (100 mL) was added 15% aqueous sodium methyl mercaptan solution(61 mL, 190 mmol) under nitrogen atmosphere at room temperature, and themixture was warmed to 60° C. and stirred for 2 hours. The mixture wasconcentrated under reduced pressure, and the residue was extracted twicewith diethyl ether (50 mL), sequentially washed with water (50 ml) andsaturated aqueous sodium chloride solution (50 mL), and dried oversodium sulfate. The resultant mixture was filtrated and the solvent wasevaporated to give the title compound (16 g, yield 99%) as a colorlessoil.

PREPARATION EXAMPLE 1-2(1R*,2R*)-(1-chloro-1-methyl-2-methylsulfanyl-propyl)benzene or(1R*,2R*)-(2-chloro-1-methyl-1-methylsulfanyl-propyl)benzene (Step 1-2)

To a solution of (2R,3R)-3-methylsulfanyl-2-phenyl-butan-2-ol (1.0 g,5.1 mmol) obtained in Preparation Example 1-1 in toluene (3.0 mL) wasadded dropwise a solution of thionyl chloride (0.67 mL, 9.2 mmol) intoluene (2.0 mL) under argon atmosphere at 0° C., and the mixture wasstirred for 1 hour. The solution was evaporated to give a mixture of twokinds of regioisomers of the title compound (1.0 g, yield 100%) as ayellow oil.

PREPARATION EXAMPLE 1-31-(1-chloro-1-methyl-2-methylsulfanyl-ethyl)-4-fluoro-benzene or1-(2-chloro-1-methyl-1-methylsulfanyl-ethyl)-4-fluoro-benzene (step 1-3)

This procedure was performed according to the method described inSynthesis (1980, 9690-9691).

While cooling to −40° C., sulfuryl chloride (2.9 mL, 37 mmol) was addeddropwise to a solution of dimethyl disulfide (3.3 mL, 37 mmol) in1,2-dimethoxyethane (20 mL) under nitrogen atmosphere, and the mixturewas stirred for 10 min. The obtained solution was added dropwise to asolution of 4-fluoro-α-methylstyrene (10 g, 73 mmol) in1,2-dimethoxyethane (20 mL) while maintaining a temperature below −30°C. After stirring for 1 hour at room temperature, the solution wasevaporated to give a crude product of the title compound. The obtainedproduct was used in the next step without further purification.

PREPARATION EXAMPLE 1-4 diethyl2-{1-(4-fluorophenyl)-1-methyl-2-methylsulfanyl-ethyl}malonate (step1-4)

This procedure was performed according to the method described inSynthesis (1980, 9690-9691).

To a solution of diethyl malonate (12 mL, 81 mmol) in ethanol (40 mL)was added dropwise 21% sodium ethoxide ethanol solution (29 mL, 77 mmol)under nitrogen atmosphere under ice-cooling. The mixture was warmed toroom temperature, stirred for 1 hour, and cooled again with ice. Thecrude product (73 mmol) of1-(1-chloro-1-methyl-2-methylsulfanyl-ethyl)-4-fluorobenzene or1-(2-chloro-1-methyl-1-methylsulfanyl-ethyl)-4-fluorobenzene obtained inExample 1-3 was added dropwise to the mixture while maintaining atemperature below 4° C. The obtained solution was stirred for 1 hour atroom temperature and concentrated under reduced pressure. The residuewas neutralized by adding a 2N aqueous hydrochloric acid solution andthe aqueous layer was extracted with ethyl acetate (50 mL). The organiclayer was dried over magnesium sulfate, filtrated and the solvent wasevaporated. Then the obtained residue was purified by silica gelchromatography (hexane:ethyl acetate 20:1 to 5:1) to give the titlecompound (24 g, yield 84%) as a pale-yellow oil.

PREPARATION EXAMPLE 1-5[3,3-bis-ethoxycarbonyl-2-(4-fluorophenyl)-2-methylpropyl]dimethylsulfoniump-toluenesulfonate (step 1-5)

This procedure was performed according to the method described inSynthesis (1980, 9690-9691).

Diethyl 2-{1-(4-fluorophenyl)-1-methyl-2-methylsulfanylethyl}malonate(1.0 g, 2.9 mmol) obtained in Preparation Example 1-4 and methylp-toluenesulfonate (0.47 mL, 3.1 mmol) were mixed under nitrogenatmosphere, and the mixture was stirred for 12 hours at 100° C. Theobtained solution was cooled to room temperature to give a crude productof the title compound as a pale-yellow oil. The obtained product wasused in the next step without purification.

PREPARATION EXAMPLE 1-62-(4-fluorophenyl)-2-methyl-cyclopropane-1,1-dicarboxylic acid diethylester (step 1-6)

This procedure was performed according to the method described inSynthesis (1980, 9690-9691).

Under ice-cooling and under nitrogen atmosphere, a solution of 21%sodium ethoxide in ethanol (1.6 mL, 4.4 mmol) was added to a solution ofthe crude product (2.9 mmol) of{3,3-bis-ethoxycarbonyl-2-(4-fluorophenyl)-2-methylpropyl}dimethylsulfoniump-toluenesulfonate in ethanol (10 mL), which was obtained in PreparationExample 1-5, and the mixture was stirred for 1 hour. The obtainedsolution was concentrated under reduced pressure, and the residue wasneutralized by the addition of a 2N aqueous hydrochloric acid solution,and the aqueous layer was extracted with ethyl acetate (10 mL). Theorganic layer was dried over magnesium sulfate and filtrated, and thesolvent was evaporated. Then, the obtained residue was purified bysilica gel chromatography (hexane:ethyl acetate=20:1 to 5:1) to give thetitle compound (0.64 g, yield 75%) as a pale-yellow oil.

PREPARATION EXAMPLE 1-7 2-methyl-2-phenyl-cyclopropane-1,1-dicarboxylicacid diethyl ester (step 1-7)

This procedure was performed according to the method described in Bull.Chem. Soc. Jpn. (1982, 55, 2687-2688).

To a solution of α-methylstyrene (570 mL, 4.4 mol),1,8-diazabicyclo[5.4.0]undec-7-ene (240 mL, 1.6 mol) and copper (II)bromide (9.8 g, 44 mmol) in toluene (700 mL) was added diethylbromomalonate (210 g, 0.88 mol) at 0° C., and the mixture was stirredfor 22 hours at room temperature. The obtained solution was washed withsaturated aqueous ammonium chloride solution and saturated aqueoussodium chloride solution, and dried over sodium sulfate. Then, thesolution was filtrated and the solvent was evaporated. The obtainedresidue was separated and purified by silica gel chromatography(hexane:ethyl acetate=20:1) to give the title compound (110 g, yield45%) as a colorless oil.

PREPARATION EXAMPLE 1-7-2(2R*,3R*)-2-methyl-3-phenyl-cyclopropane-1,1-dicarboxylic acid dimethylester (step 1-7)

This procedure was performed according to the method described inSynlett (2001, 12, 1843-1846).

To a mixture of bis(methoxycarbonyl)(phenyliodono)methanide (30 g, 90mmol) synthesized by a known method and cis-p-methylstylene (60 g) wasadded rhodium (II) acetate dimer (0.16 g, 0.72 mmol). After stirring for20 min. at 120° C., the mixture was concentrated under reduced pressure.The procedure was repeated twice, and the obtained residues werecombined. Then a mixed solvent of hexane:ethyl acetate=5:1 (360 mL) andsilica gel (30 g) were added, and the mixture was stirred for 30 min.Silica gel was removed and the mixture was concentrated under reducedpressure to give the title compound (38 g, yield 85%) as a pale-yellowoil.

PREPARATION EXAMPLE 1-8 (R)-2-benzyl-cyclopropane-1,1-dicarboxylic aciddimethyl ester (step 1-8)

A solution of (S)-4-benzyl-[1,3,2]dioxathiolane 2,2-dioxide (1.6 g, 7.5mmol) in 1,2-dimethoxyethane (12 mL), which was synthesized from diolobtained by reducing L-phenyllacetic acid according to J. Am. Chem. Soc.(1988, 110, 7538-7539), and dimethyl malonate (0.86 mL, 7.5 mmol) wasadded dropwise to a suspension of sodium hydride (liquid paraffin 40%added, 0.63 g, 16 mmol) in 1,2-dimethoxyethane (25 mL) under argonatmosphere at 0° C. The mixture was warmed to room temperature andstirred for 2.5 hours. To the obtained solution was added saturatedaqueous ammonium chloride solution (20 mL). The organic layer wasextracted twice with diethyl ether (10 mL), washed with saturatedaqueous sodium chloride solution (30 mL), and dried over sodium sulfate.After filtration and evaporation, the obtained residue was purified bysilica gel chromatography (hexane:ethyl acetate=9:1) to give the titlecompound (0.88 g, yield 47%).

PREPARATION EXAMPLE 1-9 a) t-butyl(Z)-3-phenyl-allyl 2-diazomalonate

To malonic acid t-butyl ester (Z)-3-phenyl allyl ester (15 g. 54 mmol)was added tolylsulfonylazide (12 g, 60 mmol), K₂CO₃ (8.3 g, 60 mmol) inacetonitrile (110 mL). After stirring overnight at room temperature, thereaction mixture was concentrated and diluted with EtOAc. After washingwith water (×2) and brine and drying over Na₂SO₄, a crude product waspurified by column chromatography using 10:1 hexanes/EtOAc to afford 16g (100%) of the desired product.

b) (1R*,5R*,6R*)-2-oxo-6-phenyl-3-oxa-bicyclo[3.1.0]hexane-1-carboxylicacid t-butyl ester (step 1-9)

To the 2-diazomalonic acid t-butyl ester (Z)-3-phenyl-allyl ester (16 g,54 mmol) above were added triethyl phosphite (0.090 g, 0.54 mmol) andcopper (I) iodide (0.10 g, 0.54 mmol) in toluene (490 mL). After heatingat 130° C. for 5 hours, the solid was filtered off and the filtrate wasconcentrated. The reaction mixture was purified by column chromatographyusing dichloromethane as an eluent. Purification afforded 5.2 g of thedesired diastereomer and 2.8 g of the other diastereomer.

PREPARATION EXAMPLE 1-102-(3-benzyloxyphenyl)-cyclopropane-1,1-dicarboxylic acid dimethyl ester(step 1-10)

This procedure was performed according to the method described in J.Med. Chem. (1992, 35, 1410-1417).

While water-bathing, to a suspension of sodium hydride (liquid paraffin40% added, 5.0 g, 0.13 mol) in dimethyl sulfoxide (180 mL) was graduallyadded trimethylsulfoxonium iodide (28 g, 0.13 mmol) under argonatmosphere, and the mixture was stirred for 30 min. Then dimethyl2-(3-benzyloxybenzylidene)malonate (37 g, 0.11 mol) synthesized by themethod described in the above-mentioned reference was added dropwise.After stirring for 1 hour at 50° C., saturated aqueous ammonium chloridesolution (200 mL) and toluene (100 mL) were added to the obtainedsolution. The mixture was separated into layers and extracted withtoluene (100 mL). The organic layer was sequentially washed with water(100 mL) and saturated aqueous sodium chloride solution (20 mL) anddried over magnesium-sulfate. After filtration and evaporation, theobtained residue was separated and purified by silica gel chromatography(hexane:chloroform=4:1) to give the title compound (31 g, 79%) as apale-yellow oil.

PREPARATION EXAMPLE 1-11(1R*,2R*,3R*)-2-methyl-3-phenylcyclopropane-1,1-dicarboxylic acidmono-methyl ester (step 1-11)

To a solution of(2R*,3R*)-2-methyl-3-phenylcyclopropane-1,1-dicarboxylic acid dimethylester (39 g, 0.16 mol) obtained in Preparation Example 1-7-2 in methanol(390 mL) was added 4N aqueous sodium hydroxide solution (160 mL, 0.62mol) at 0° C., and the mixture was stirred for 18 hours at roomtemperature. After the mixture was concentrated under reduced pressure,diethyl ether and water were added and the mixture was stirred. Afterthe organic layer was removed, concentrated hydrochloric acid was addedto the aqueous layer under ice-cooling until the pH level read about 1.The organic layer was extracted with ethyl acetate, washed withsaturated aqueous sodium chloride solution, and dried over sodiumsulfate. The solution was filtrated and the solvent was evaporated. Theobtained crude product was azeotroped with toluene, and diethyl etherand hexane were added gradually. The precipitated crystals werefiltrated and dried under reduced pressure to give the title compound(35 g, yield 96%) as while crystals.

PREPARATION EXAMPLE 1-11-2(1R*,5S*,6S*)-2-oxo-6-phenyl-3-oxa-bicyclo[3.1.0]hexane-1-carboxylicacid (step 1-11)

To 0.18 g (0.65 mmol) of(1R*,5R*,6R*)-2-oxo-6-phenyl-3-oxa-bicyclo[3.1.0]hexane-1-carboxylicacid t-butyl ester were added 1 mL of trifluoroacetic acid and 2 mL ofdichloroethane. After stirring at room temperature for 20 min. thereaction mixture was concentrated and dried under high vacuum to afford0.14 g (98%) of the desired acid.

PREPARATION EXAMPLE 1-11-3 a)(1R*,2R*,3R*)-2-hydroxymethyl-1-(methoxy-methyl-carbamoyl)-3-phenyl-cyclopropanecarboxylicacid t-butyl-ester

In a 100 mL round-bottomed flask, a solution of N,O-dimethylhydroxylamine HCl was suspended in 20 mL of dichloromethane. Aftercooling to 0° C., trimethyl aluminum (2M in toluene, 3.83 mL, 7.66 mmol)was added dropwise and the mixture was stirred at 0° C. for 45 min. Asolution of the previously described(1R*,5R*,6R*)-2-oxo-6-phenyl-3-oxa-bicyclo[3.1.0]hexane-1-carboxylicacid tert-butyl ester (0.3 g, 1 mmol) in 10 mL of dichloromethane wasadded dropwise to the cooled stirring solution. After stirring at 0° C.for 5 min, the reaction mixture was warmed to room temperature andstirred for 3 hours. After the reaction was completed, the reactionmixture was again cooled in an ice bath and acidified with 10 mL of 1NHCl, extracted with dichloromethane (×3), dried over MgSO₄ andconcentrated to afford 0.32 g (86%) of the desired product as a clearoil.

b)(1R,2R*,3R*)-2-methoxymethyl-1-(methoxy-methyl-carbamoyl)-3-phenyl-cyclopropanecarboxylicacid t-butyl ester

The above(1R*,2R*,3R*)-2-hydroxymethyl-1-(methoxy-methyl-carbamoyl)-3-phenyl-cyclopropanecarboxylicacid t-butyl ester (0.050 g, 0.15 mmol) was dissolved in 1 mL of methyliodide. To this solution was added silver oxide (0.69 g, 3.0 mmol) andthe mixture was stirred overnight at room temperature under N₂ (in thedark). This reaction was incomplete and additional methyl iodide andsilver oxide were added. After stirring overnight, the reaction appearedstalled. The catalyst was filtered off through celite and the residuewas rinsed with ether. The filtrate was concentrated to a clear oil andpurified by prep-TLC using 1:1 hexanes/EtOAc to afford 30 mg of thedesired product (58%). This reaction was repeated numerous times tobring up more material. Note: If a huge excess of silver oxide was notused, the reaction often led to a reversion to the lactone product.

c)(1R*,2R*,3R*)-2-methoxymethyl-1-(methoxy-methyl-carbamoyl)-3-phenyl-cyclopropanecarboxylicacid (step 1-11)

(1R*,2R*,3R*)-2-methoxymethyl-1-(methoxy-methyl-carbamoyl)-3-phenyl-cyclopropanecarboxylicacid t-butyl ester (30 mg, 0.086 mmol) was dissolved in 1 mL oftrifluoroacetic acid and 1 mL of dichloromethane. After stirring at roomtemperature for 2 hours, the reaction mixture was concentrated andazeotroped with toluene. The product was dried under high vacuum beforeuse.

PREPARATION EXAMPLE 1-12(1R*,2S*,3S*)-1-t-butoxycarbonylamino-2-methyl-3-phenyl-cyclopropanecarboxylicacid methyl ester (step 1-12)

To a solution of 2-methyl-3-phenylcyclopropane-1,1-dicarboxylic acidmono-methyl ester (36 g, 0.16 mol) obtained in Preparation Example 1-11and triethylamine (35 mL, 0.25 mol) in t-butylalcohol (370 mL) was addeddiphenylphosphoryl azide (44 mL, 0.20 mol). After stirring for 2 hoursat room temperature, the mixture was warmed gradually and refluxed for 7hours. After the solvent was evaporated under reduced pressure, a mixedsolvent of hexane:ethyl acetate=4:1 (750 mL) and silica gel (200 g) wereadded and the mixture was stirred for 30 min. Then silica gel wasremoved, and the mixture was concentrated under reduced pressure. Hexanewas added to the obtained residue, and the precipitated crystals werefiltrated to give the title compound (35 g, yield 74%) as a white solid.

PREPARATION EXAMPLE 1-12-2{(1R*,5R*,6R*)-2-oxo-6-phenyl-3-oxa-bicyclo[3.1.0]hexa-1-yl}carbamicacid t-butyl ester (step 1-12)

To 0.20 g (0.92 mmol) of(1R*,5S*,6S*)-2-oxo-6-phenyl-3-oxa-bicyclo[3.1.0]hexane-1-carboxylicacid were added diphenylphosphoryl azide (0.33 g, 1.2 mmol) anddiisopropylethylamine (0.32 mL, 1.8 mmol) in tert-butyl alcohol. Afterheating at ˜90° C. for 2 hours, the reaction mixture was concentratedand purified using column:chromatography (3:1 hexanes/EtOAc). Thedesired product was isolated as a white solid (0.23 g, yield 85%).

PREPARATION EXAMPLE 1-12-3{(1R*,2R*,3R*)-2-methoxymethyl-1-(methoxy-methyl-carbamoyl)-3-phenyl-cyclopropyl}carbamicacid t-butyl ester (step 1-12)

(1R*,2R*,3R*)-2-methoxymethyl-1-(methoxy-methyl-carbamoyl)-3-phenyl-1-cyclopropanecarboxylicacid (0.10 g, 0.34 mmol) was dissolved in 8 mL of t-butyl alcohol. Tothis solution were added diisopropylethylamine (0.15 g, 0.85 mmol) and 4Å molecular sieves. Then diphenylphosphoryl azide (0.11 mL, 0.51 mmol)was added in one portion. The reaction mixture was heated to 90° C.overnight. After cooling, the reaction mixture was poured into saturatedNaHCO₃ and extracted with EtOAc (2×). The combined organic layers werewashed with brine and dried over MgSO₄. The crude product was purifiedusing column chromatography (5:1->1:1 hexanes/EtOAc gradient) to affordthe desired product (stains slightly with KMnO₄ stain). A white solid(69 mg, 56% yield) was isolated, which contained about 50% desiredproduct and 50% lactone. This material was carried through to the nextstep. NOTE: the above reaction was run in very dilute t-butyl alcoholand using 4 Å molecular sieves to prevent formation of free amine andsubsequent self-condensation to form a urea byproduct.

PREPARATION EXAMPLE 2-12-[2-(t-butyldiphenylsilanyloxy)ethyl]-2-phenyl-cyclopropane-1,1-dicarboxylicacid dimethyl ester (step 2-1)

To a mixture of t-butyldiphenyl-(3-phenyl-3-butenyloxy)-silane (3.0 g,7.0 mmol) and dimethyl diazomalonate (1.1 g, 7.0 mmol), which wassynthesized by the method described in Synth. Commun. (1987, 17,1709-1716), was added rhodium (II) acetate dimmer (62 mg, 0.14 mmol)under argon atmosphere, and the mixture was heated at 100° C. for 10min. After cooling to room temperature, the mixture was diluted withchloroform (4 mL), separated and purified by silica gel chromatography(hexane:ethyl acetate=100:0 to 4:1) to give the title compound (2.5 g,yield 70%) as a colorless oil.

PREPARATION EXAMPLE 2-2(1R*,6R*)-2-oxo-6-phenyl-3-oxa-bicyclo[4.1.0]heptan-1-carboxylic acidmethyl ester (step 2-2)

To a solution of2-[(2-(t-butyldiphenylsilanyloxy)ethyl]-2-phenyl-cyclopropane-1,1-dicarboxylicacid dimethyl ester (1.3 g, 2.5 mmol) obtained in Preparation Example2-1 in tetrahydrofuran (13 mL) was added tetrabutylammonium fluoridetrihydrate (1.2 g, 3.7 mmol) under argon atmosphere at 0° C., and themixture was stirred at room temperature for 12 hours. The obtainedsolution was diluted with ethyl acetate and washed with saturatedaqueous sodium chloride solution. The aqueous layer was extracted twicewith ethyl acetate, and the combined organic layers were dried oversodium sulfate. After filtration and evaporation, the obtained residuewas separated and purified by silica gel chromatography (hexane:ethylacetate=10:1 to 1:1) to give the title compound (0.41 g, yield 67%) as awhite solid.

PREPARATION EXAMPLE 2-3(1R*,5S*)-2-oxo-5-phenyl-3-oxa-bicyclo[3.1.0]hexane-1-carboxylic acidt-butyl ester (step 2-3)

Under nitrogen atmosphere, potassium t-butoxide (110 g, 0.78 mol) wasadded to a solution of di-t-butyl malonate (170 g, 0.78 mol) in t-butylalcohol (1.5 L) in 3 portions at room temperature. After stirring atroom temperature for 1 hour, the mixture was heated to 70° C. Then asolution of 2-chloromethyl-2-phenyloxirane (120 g) in tetrahydrofuran(500 mL) synthesized by the method described in J. Org. Chem. (1962, 27,2241-2243) was added dropwise over 90 min. After stirring for 12 hoursat 70° C., the mixture was cooled to room temperature and the solventwas evaporated. 10% Aqueous citric acid solution (500 mL) was added tothe residue. The mixture was extracted with ethyl acetate (2.0 L),sequentially washed with water (500 mL) and saturated aqueous sodiumchloride solution (200 mL), and dried over magnesium sulfate. Afterfiltration and evaporation, the title compound (120 g, 3 step, yield54%) was recrystallized from a mixed solution of hexane:diisopropylether=1:1 (600 mL) as a white solid.

PREPARATION EXAMPLE 2-3-2(1R,5S)-2-oxo-5-phenyl-3-oxa-bicyclo[3.1.0]hexane-1-carboxylic acidt-butyl ester (step 2-3)

To a suspension of the starting material (7.0 g, 32 mmol) obtained bydeprotecting t-butyl group of(1R*,5S*)-2-oxo-5-phenyl-3-oxa-bicyclo[3.1.0]hexane-1-carboxylic acidt-butyl ester obtained in Preparation Example 2-3 in ethanol (210 mL)was added quinidine (10 g, 32 mmol) at room temperature. After stirringat room temperature for 5 hours, the resultant precipitate was filtratedto give an optically active compound as a quinidine salt. The quinidinesalt was suspended in ethyl acetate (80 mL) and water (60 mL). Then 1Naqueous hydrochloric acid solution (20 mL, 20 mmol) was added to thesuspension at 0° C. and the mixture was stirred. After the organic layerwas washed with saturated aqueous sodium chloride solution and driedover magnesium sulfate, an optically active carboxylic acid compound(3.3 g, yield 47%, optical purity 96% ee) was obtained as a whiteamorphous form after filtration and evaporation. The compound wasesterificated in a similar manner as in Example 5-2 to give the titlecompound {4.0 g, yield 95%, [α]²⁵ _(D) −62.9° (c 0.275, MeOH)} as whitecrystals.

PREPARATION EXAMPLE 2-4 a) sodium(1R*,2S*)-1-t-butoxycarbonyl-2-hydroxymethyl-2-phenyl-cyclopropanecarboxylate

To a solution of(1R*,5S*)-2-oxo-5-phenyl-3-oxa-bicyclo[3.1.0]hexane-1-carboxylic acidt-butyl ester (30 g, 0.11 mol) obtained in Preparation Example 2-3 intetrahydrofuran (300 mL) was added 4N aqueous sodium hydroxide solution(29 mL, 0.11 mol) at room temperature.

After stirring at 60° C. for 2.5 hours, the mixture was concentratedunder reduced pressure. Then the mixture was azeotroped with toluene toremove water. The title compound (39 g) was obtained as a whiteamorphous form. The obtained product was used in the next step withoutpurification.

b)(1R*,2S*)-2-(t-butyldimethylsilanyloxymethyl)-2-phenyl-cyclopropane-1,1-dicarboxylicacid mono-t-butyl ester (step 2-4)

Imidazol (18 g, 0.27 mol) was added to a suspension of sodium(1R*,2S*)-1-t-butoxycarbonyl-2-hydroxymethyl-2-phenyl-cyclopropanecarboxylate(38 g, 0.11 mol) obtained in the above-mentioned Example a) inN,N-dimethylformamide (190 mL) under argon atmosphere at 0° C., andt-butyldimethylsilyl chloride (35 g, 0.24 mol) was further added in 2portions. After warming to room temperature, the mixture was stirred for12 hours. Then water (76 mL) and methanol (76 mL) were added to themixture at 0° C., which was followed by addition of potassium carbonate(30 g, 0.21 mol). After the obtained suspension was stirred for 3 hoursat room temperature, toluene (190 mL) was added and the mixture wasseparated into layers using 10% aqueous citric acid solution (400 mL)while adjusting pH to about 5. The aqueous layer was extracted twicewith toluene, and the combined organic layer was sequentially washedwith 10% aqueous citric acid solution and saturated aqueous sodiumchloride solution, and dried over sodium sulfate. After filtration andevaporation, the product was azeotroped with xylene to removet-butyldimethylsilanol. The title compound (44 g) was obtained as whitecrystals. The obtained product was used in the next step withoutpurification.

PREPARATION EXAMPLE 2-4-2(1R*,2S*)-cis-1-carbamoyl-2-(2-hydroxyethyl)-2-phenylcyclopropanecarboxylicacid methyl ester PREPARATION EXAMPLE 2-4

To a solution of(1R*,6R*)-2-oxo-6-phenyl-3-oxa-bicyclo[4.1.0]heptan-1-carboxylic acidmethyl ester (0.29 g, 1.2 mmol) obtained in Preparation Example 2-2 in atetrahydrofuran:methanol=1:1 mixture (6 mL) was added 28% ammonia inwater (6 mL) at room temperature, and the mixture was stirred for 12hours. The obtained solution was concentrated under reduced pressure togive the title compound (0.32 g) as a colorless oil. The obtainedproduct was used in the next step without purification.

PREPARATION EXAMPLE 2-5(1R*,6R*)-3-oxo-6-phenyl-4-oxa-2-aza-bicyclo[4.1.0]heptan-1-carboxylicacid t-butyl ester PREPARATION EXAMPLE 2-5

To a solution of(1R*,2S*)-2-(t-butyldimethylsilanyloxymethyl)-2-phenyl-cyclopropane-1,1-dicarboxylicacid mono-t-butyl ester (42 g, 0.10 mol) obtained in Preparation Example2-4 in N,N-dimethylformamide (310 mL) were sequentially addedtriethylamine (15 mL, 0.11 mol) and diphenylphosphoryl azide (24 mL,0.11 mol) under argon atmosphere. After stirring at 80° C. for 30 min.,the mixture was cooled to room temperature over 1 hour. Then, cesiumfluoride (30 g, 0.20 mol) was added at once, and the mixture was stirredat 50° C. for 1.5 hours. To the obtained suspension were added water(300 mL), toluene (150 mL), diethyl ether (0.150 mL) and tetrahydrofuran(100 mL), and the insoluble solid was filtrated. The filtrate wasseparated into layers, and the aqueous layer was extracted twice withtoluene. The residue was sequentially washed with 1N aqueous sodiumhydroxide solution and water and dried over sodium sulfate. Afterfiltration and evaporation, the obtained residue and the above-mentionedsolid were combined. A mixed solvent of hexane:diisopropyl ether=2:1(150 mL) was added and the mixture was stirred at room temperature for30 min. After the obtained crystal was filtrated, the residue was driedunder reduced pressure to give the title compound (21 g, 3 steps, yield73%) as a white solid.

PREPARATION EXAMPLE 2-5-2(1R*,7R*)-3-oxo-7-phenyl-4-oxa-2-azabicyclo[5.1.0]octane-1-carboxylicacid methyl ester (step 2-5)

To a solution of(1R*,2S*)-cis-1-carbamoyl-2-(2-hydroxyethyl)-2-phenylcyclopropanecarboxylicacid methyl ester (0.30 g, 1.1 mmol) obtained in Preparation Example2-4-2 in an ethyl acetate:acetonitrile:water=1:2:1 mixture (12 mL) wasadded iodobenzene diacetate (0.48 g, 1.5 mmol) at 0° C. After stirringat room temperature for 1.5 hours, iodobenzene diacetate (64 mg, 0.23mmol) was further added, and the mixture was stirred for 1.5 hours.After the obtained solution was diluted with ethyl acetate and separatedinto layers, the aqueous layer was extracted twice with ethyl acetate.The combined organic layers were washed with saturated aqueous sodiumchloride solution, and dried over sodium sulfate. After filtration andevaporation, the obtained residue was separated and purified by silicagel chromatography (hexane:ethyl acetate=40:1 to 1:2) to give the titlecompound (0.11 g, 35%) as a white solid.

PREPARATION EXAMPLE 2-6(1R*,2R*)-1-t-butoxycarbonylamino-2-hydroxymethyl-2-phenylcyclopropanecarboxylicacid t-butyl ester step 2-6)

To a solution of(1R*,6R*)-3-oxo-6-phenyl-4-oxa-2-aza-bicyclo[4.1.0]heptan-1-carboxylicacid t-butyl ester (2.0 g, 6.9 mmol) obtained in Preparation Example 2-5in tetrahydrofuran (40 mL) was added sodium hydride (liquid paraffin 40%added, 0.61 g, 15 mmol) under nitrogen atmosphere at 0° C., and themixture was stirred for 30 min. Then a solution of di-t-butyldicarbonate (2.4 g, 11 mmol) in tetrahydrofuran (20 mL) was addeddropwise to the obtained solution. After stirring at 0° C. for 5 min.,the mixture was warmed to room temperature and stirred for 20 hours.Then, acetic acid (1 mL) and water (30 mL) were added to theobtained-solution, and the solution was extracted three times with ethylacetate (50 mL). The residue was washed with water (30 mL) and saturatedaqueous sodium chloride solution (30 mL), and dried over sodium sulfate.After filtration and evaporation, hexane (20 mL) was added to theobtained residue to allow precipitation of crystals. The crystals werefiltrated and dried under reduced pressure to give(1R*,6R*)-3-oxo-6-phenyl-4-oxa-2-aza-bicyclo[4.1.0]heptan-1,2-dicarboxylicacid di-t-butyl (2.1 g) as a crude product.

To the obtained solution of(1R*,6R*)-8-oxo-6-phenyl-4-oxa-2-aza-bicyclo[4.1.0]heptan-1,2-dicarboxylicacid di-t-butyl ester (2.1 g, 5.5 mmol) in methanol (42 mL) was addedcesium carbonate (0.54 g, 1.7 mmol) at room temperature. After stirringfor 30 min., the mixture was concentrated to about half the amount underreduced pressure, and then saturated aqueous sodium chloride solution(40 mL) was added to the obtained residue. The mixture was extractedthree times with ethyl acetate (30 mL), washed with water (50 mL) andsaturated aqueous sodium chloride solution (50 mL), and dried oversodium sulfate. After filtration and evaporation, hexane (20 mL) wasadded to the obtained residue to allow precipitation of crystals. Thecrystals were filtrated and dried under reduced pressure to give thetitle compound (1.9 g, yield 74%) as a colorless amorphous form.

PREPARATION EXAMPLE 3-1 (1R*,2S*)-1-amino-2-vinyl-cyclopropanecarboxylicacid ethyl ester (step 3-1)

The title compound was synthesized according to the method described inWO0009543.

PREPARATION EXAMPLE 4-11-amino-1,1a,2,3,4,8b-hexahydrobenzo[a]cyclopropa[c]cyclohepten-1-carboxylicacid ethyl ester (step 4-1)

Nitroethyl acetate (3.8 mL, 34 mmol), rhodium (II) pivalate dimmer (0.11g, 0.17 mmol) and iodobenzene diacetate (12 g, 38 mmol) were graduallyadded to 6,7-dihydro-5H-benzocycloheptene (5.0 g, 35 mmol) synthesizedby the method described in J. Chem. Soc. Chem. Commun. (1990, 18,1270-1271) under argon atmosphere, and the mixture was stirred at 40° C.for 14 hours. The obtained solution was cooled to room temperature, andseparated and purified by silica gel chromatography (hexane:ethylacetate=20:1) to give1-nitro-1,1a,2,3,4,8b-hexahydrobenzo[a]cyclopropane[c]cyclohepten-1-carboxylicacid ethyl ester (1.5 g, yield 17%).

To the obtained solution of1-nitro-1,1a,2,3,4,8b-hexahydrobenzo[a]cyclopropane[c]cyclohepten-1-carboxylicacid ethyl ester (1.9 g, 7.0 mmol) in isopropylalcohol (140 mL) weregradually added aqueous solution of 1N hydrochloric acid (70 mL, 70mmol) and zinc powder (9.1 g, 0.14 mol), and the mixture was stirred atroom temperature for 4 hours. The obtained solution was cooled to 0° C.Then, saturated aqueous sodium hydrogen carbonate solution (150 mL) wasadded to the solution, and the mixture was filtrated. After the filtratewas separated into layers, the aqueous layer was extracted twice withethyl acetate (100 mL) and dried over magnesium sulfate. Afterfiltration and evaporation, the obtained residue was separated andpurified by silica gel chromatography (chloroform:methanol=30:1) to givethe title compound (1.5 g, yield 87%) as a pale-yellow oil.

PREPARATION EXAMPLE 5-1(1R*,2S*,3S*)-1-t-butoxycarbonylamino-2-methyl-3-phenyl-cyclopropanecarboxylicacid (step 5-1)

To a solution of(1R*,2S*,3S*)-1-t-butoxycarbonylamino-2-methyl-3-phenyl-cyclopropanecarboxylicacid methyl ester (37 g, 0.12 mol) obtained in Preparation Example 1-12in a methanol:tetrahydrofuran=15:1 mixture (610 mL) was added 4N aqueoussodium hydroxide solution (95 mL, 0.38 mol), and the mixture wasrefluxed for 6 hours. The mixture was allowed to cool to roomtemperature and the solvent was evaporated. 4N aqueous hydrochloric acidsolution was added to the residue at 0° C. until the pH level read about3. After the aqueous layer was extracted with ethyl acetate (800 mL),the organic layer was washed with saturated aqueous sodium chloridesolution. The solution was dried over magnesium sulfate and the solventwas evaporated under reduced pressure to give the title compound (38 g)as a crude product of a pale-yellow oil. The obtained product was usedin the next step without further purification.

PREPARATION EXAMPLE 5-1-2(1S,2R,3R)-1-t-butoxycarbonylamino-2-methyl-3-phenyl-cyclopropanecarboxylicacid (step 5-1)

To a solution of(1R*,2S*,3S*)-1-t-butoxycarbonylamino-2-methyl-3-phenyl-cyclopropanecarboxylicacid (38 g) obtained in Preparation Example 5-1 in isopropylalcohol (380mL) was added quinidine (40 g, 0.12 mmol), and the mixture was stirredat room temperature for 20 hours. The obtained crystal was filtrated togive an optical active quinidine salt (28 g, 44 mmol) as a white solid.The quinidine salt was suspended in ethyl acetate (250 mL) and water(250 mL), and the suspension was stirred after addition of 1N aqueoushydrochloric acid solution (88 mL, 88 mmol) at 0° C. The organic layerwas washed with saturated aqueous sodium chloride solution, and driedover magnesium sulfate. The title compound {13 g, 2 steps, yield 37%,[α]²⁵ _(D) +111° (c 1.00, MeOH), optical purity 97% ee} was obtained asa white amorphous form by filtration and evaporation.

PREPARATION EXAMPLE 5-2(1S,2R,3R)-1-t-butoxycarbonylamino-2-methyl-3-phenyl-cyclopropanecarboxylicacid t-butyl ester (step 5-2)

Under argon atmosphere, N,N-dimethylformamide di-t-butylacetal (5.0 mL,21 mmol) was added dropwise to a solution of(1S,2R,3R)-1-t-butoxycarbonylamino-2-methyl-3-phenyl-cyclopropanecarboxylicacid (1.5 g, 5.2 mmol) obtained in Preparation Example 5-1 in toluene(15 mL) at 80° C. over 15 min, and the mixture was stirred for 1 hour.The obtained solution was cooled to 0° C. After saturated aqueous sodiumhydrogen carbonate solution (15 mL) was added to the mixture, theorganic layer was washed three times with water (10 mL) and driedover-magnesium sulfate. Then, the title compound (1.8 g, yield 99%) wasobtained as a pale-yellow oil by filtration and evaporation. Theobtained product was used in the next step without further purification.

PREPARATION EXAMPLE 5-3(1R*,2S*)-1-t-butoxycarbonylamino-2-[2-(2-ethoxycarbonyl-ethyl)-phenyl]-cyclopropanecarboxylicacid methyl ester (step 5-3)

To a solution of(1R*,2S*)-2-(2-bromo-phenyl)-1-t-butoxycarbonylamino-cyclopropanecarboxylicacid methyl ester (50 mg, 0.14 mmol) obtained in a similar manner asdescribed in Preparation Example 1-12 in tetrahydrofuran (0.5 mL) wereadded dibenzylidene acetone palladium (7.8 mg, 14 μmol),1,2,3,4,5-pentaphenyl-1′-(di-t-butylphosphino) ferrocene (9.6 mg, 14μmol) and 0.5M solution of 3-ethoxy-3-oxopropylzinc bromide intetrahydrofuran (0.81 mL, 0.41 mmol), and the mixture was stirred atroom temperature for 2 hours. To the mixture were added 1N aqueoushydrochloric acid solution (0.5 mL) and water (5.0 mL), and the mixturewas extracted twice with ethyl acetate (10 mL). Then the organic layerwas sequentially washed with water (5.0 mL) and saturated aqueous sodiumchloride solution (5.0 mL), and dried over magnesium sulfate. Afterfiltration and evaporation, the obtained residue was separated andpurified by silica gel chromatography (hexane:ethyl acetate=5:1) to givethe title compound (50 mg, yield 95%) as a brown oil.

PREPARATION EXAMPLE 5-4(1S,2R,3R)-1-amino-2-methyl-3-phenyl-cyclopropanecarboxylic acid-t-butylester (step 5-4)

Under argon atmosphere, p-toluenesulfonic acid monohydrate (3.5 g, 18mmol) was added to a solution of(1S,2R,3R)-1-t-butoxycarbonylamino-2-methyl-3-phenyl-cyclopropanecarboxylicacid t-butyl ester (3.2 g, 9.1 mmol) obtained in Preparation Example 5-2in acetonitrile (30 mL) at 0° C., and the mixture was stirred at roomtemperature for 16 hours. The obtained solution was cooled to 0° C., and1N aqueous sodium hydroxide solution (20 mL) was added. The aqueouslayer was extracted twice with ethyl acetate (15 mL) and dried overmagnesium sulfate. Then, the residue was filtrated and the solvent wasevaporated to give a crude product of the title compound (1.8 g, yield99%) as a crude product of a pale-yellow oil. The obtained product wasused in the next step without purification.

PREPARATION EXAMPLE 5-4-2(1R*,2S*)-1-amino-2-azidomethyl-2-phenyl-cyclopropanecarboxylic acidt-butyl ester (step 5-4)

p-Toluenesulfonic acid monohydrate (5.2 g, 27 mmol) was added to asolution of the crude product (5.0 g) of(1R*,2S*)-2-azidomethyl-1-t-butoxycarbonylamino-2-phenyl-cyclopropanecarboxylicacid t-butyl ester, which was made from(1R*,2S*)-1-t-butoxycarbonylamino-2-hydroxymethyl-2-phenyl-cyclopropanecarboxylicacid t-butyl ester obtained in Preparation Example 2-6 by general methodstep 5-3, in acetonitrile (40 mL). The mixture was stirred at roomtemperature for 14 hours. After water (16 mL) was added, the mixture wasfurther stirred for 7 hours and separated into layers by adding ethylacetate (50 mL). The organic layer was washed with saturated aqueoussodium hydrogen carbonate solution (30 mL), water (30 mL) and saturatedaqueous sodium chloride solution (50 mL), and dried over sodium sulfate.The residue was filtrated and the solvent was evaporated to give a crudeproduct of the title compound (2.8 g). The obtained product was used inthe next step without further purification.

PREPARATION EXAMPLE 5-4-3(1R*,5R*,6R*)-1-amino-6-phenyl-3-oxa-bicyclo[3.1.0]hexane-2-one (step5-4)

{(1R*,5R*,6R*)-2-oxo-6-phenyl-3-oxa-bicyclo[3.1.0]hex-1-yl}-carboxylicacid t-butyl ester (0.22 g, 0.76 mmol) was dissolved in 4 mL ofdichloroethane and 2 mL of trifluoroacetic acid. This reaction wasstarted at 0° C. and the reaction mixture was warmed to room temperatureover 30 min. After concentration, the reaction mixture was diluted withsaturated NaHCO₃. (5 mL) and extracted with dichloromethane (5×10 mL).The combined organic layers were washed with brine (×2), dried overNa₂SO₄ and concentrated to afford a free base as a clear oil (yield97%).

PREPARATION EXAMPLE 5-4-4(1R*,2R*,3R*)-1-amino-2-methoxymethyl-3-phenyl-cyclopropanecarboxylicacidmethoxy-methyl-amide hydrochloride (step 5-4)

[(1R*,2R*,3R*)-2-methoxymethyl-1-(methoxy-methyl-carbamoyl)-3-phenyl-cyclopropyl]-carbamicacid t-butyl ester (25 mg, 0.69 mmol) was dissolved in 4 mL of HCl indioxane (4M). After stirring at room temperature for 1 hour, thesolution was concentrated and dried under high vacuum to afford 100% ofan HCl salt product.

PREPARATION EXAMPLE 5-5(1S,2R,3R)-1-(5-bromothiophene-2-sulfonylamino)-2-methyl-3-phenylcyclopropanecarboxylicacid t-butyl ester (step 5-5)

To a solution of(1S,2R,3R)-1-amino-2-methyl-3-phenyl-cyclopropanecarboxylic acid t-butylester (2.7 g, 11 mmol) obtained in Preparation Example 5-4 in pyridine(25 mL) was added 5-bromothiophene-2-sulfonyl chloride (3.4 g, 13 mmol)at room temperature under argon atmosphere. After stirring, the mixturewas concentrated under reduced pressure. The obtained residue wasseparated and purified by silica gel chromatography (hexane:ethylacetate=10:1) to give a crude product of the title compound as apale-yellow oil. The crude product was washed with water to give thetitle compound (2.9 g, yield 58%) as a yellow solid.

PREPARATION EXAMPLE 5-5-24-[(1S,2R,3R)-1-t-butoxycarbonyl-2-methyl-3-phenyl-cyclopropylsulfamoyl]-piperazine-1-carboxylicacid t-butyl ester (step 5-5)

To a solution of chlorosulfonyl isocyanate (18 μL, 0.20 mmol) inacetonitrile (2 mL) was added 2-chloroethanol (14 μL, 0.20 mmol) at 0°C. The mixture was stirred at 0° C. for 30 min and then at roomtemperature for 1 hour. To this reaction mixture were addedN-methylmorpholine (89 μL, 0.81 mmol) and (is,2R,3R)-1-amino-2-methyl-3-phenyl-cyclopropanecarboxylic acid t-butylester (50 mg, 0.20 mmol). The reaction mixture was then stirred at 50°C. for 3 hours. This crude solution was used directly in the next step.

Under argon atmosphere, this(1S,2R,3R)-2-methyl-1-(2-oxo-oxazolidine-3-sulfonylamino)-3-phenyl-cyclopropanecarboxylicacid t-butyl ester (0.61 mmol) and t-butyl-1-piperazinecarboxylic acid(0.14 g, 0.73 mmol) were mixed, and the mixture was refluxed for 18hours under heating. The obtained solution was concentrated underreduced pressure, and the residue was purified by silica gelchromatography (hexane:ethyl acetate=10:0 to 5:1) to give the titlecompound (0.24 g, yield 79%).

PREPARATION EXAMPLE 5-6(1S,2R)-1-(6-bromomethyl-imidazo[2,1-b]thiazol-2-sulfonylamino)-2-methyl-2-phenyl-cyclopropanecarboxylicacid methyl ester (step 5-6)

To a solution of(1S,2R)-1-(2-amino-thiazol-5-sulfonylamino)-2-methyl-2-phenyl-cyclopropanecarboxylicacid methyl ester (0.21 g, 0.58 mmol) in ethyl acetate (6.4 mL) wasadded 1,3-dibromoacetone (0.18 mL, 0.87 mmol), and the mixture wasstirred at 60° C. for 18 hours. After cooling to room temperature, themixture was washed with saturated aqueous sodium hydrogen carbonatesolution and saturated aqueous sodium chloride solution, and dried oversodium sulfate. After filtration and evaporation, the obtained residuewas separated and purified by silica gel chromatography (hexane:ethylacetate=1:1) to give the title compound (68 mg, yield 24%) as apale-yellow solid.

PREPARATION EXAMPLE 5-7(1S,2R,3R)-1-[5-(4-iodo-pyrazole-1-yl)-thiophene-2-sulfonylamino-2-methyl-3-phenyl-cyclopropanecarboxylicacid t-butyl ester (step 5-7)

To a solution of(1S,2R,3R)-1-amino-2-methyl-3-phenyl-cyclopropanecarboxylic acid t-butylester (1.7 g, 6.7 mmol) obtained in Preparation Example 5-4 inchloroform (17 mL) was sequentially added triethylamine (1.4 mL, 10mmol) and 5-(4-iodo-pyrazole-1-yl)-thiophene-2-sulfonyl chloride (3.0 g,8.0 mmol) at room temperature under nitrogen atmosphere. The obtainedsolution was warmed to 50° C., and stirred for 2 hours. Then, theobtained solution was purified by silica gel chromatography(hexane:ethyl acetate=7:3) to give the title compound as a pale-yellowcrude product. The crude product was slurry-washed with diisopropylether:hexane=1:1 (30 mL) to give the title compound (3.2 g, yield 82%)as a colorless amorphous form.

PREPARATION EXAMPLE 5-10 a) 1-(3-thiophene-2-yl-isoxazole-5-yl)-ethanone

The title compound was synthesized according to the method described inknown Heterocycles (1993, 35, 591-598).

To a solution of 4-nitro-benzoic acid 1-methylene-2-oxo-propyl ester (10g, 43 mmol) synthesized by the method of Helv. Chim. Acta (1981, 64,188-197) and 2-thiophenecarbohydroxymoyl chloride (10 g, 62 mmol)synthesized by the method of Bioorg. Med. Chem. Lett. (2003, 13,1795-1799) in chloroform (100 mL) was added dropwise triethylamine (9.0mL, 62 mmol) under argon atmosphere at 0° C. over 30 min., and themixture was stirred for 30 min. Then triethylamine (6.0 mL, 42 mmol) wasadded dropwise and the mixture was warmed gradually to room temperature.

After stirring at room temperature for 12 hours, water (100 mL) wasadded to the obtained solution, and the mixture was filtrated throughcelite. The filtrate was separated into layers and extracted withchloroform (100 mL). After the organic layer was washed with 1N aqueoussodium hydroxide solution (40 mL), 1N aqueous hydrochloric acid solution(80 mL) and saturated aqueous sodium chloride solution-(40 mL) wereadded sequentially, and the mixture was dried over sodium sulfate. Afterfiltration and evaporation, the obtained residue was separated andpurified by silica gel chromatography (hexane:chloroform=1:1) to givethe title compound (5.4 g, yield 66%) as pale-brown crystals.

b) 5-(1,1-difluoroethyl)-3-thiophene-2-yl-isoxazole

Under argon atmosphere, to a suspension of1-(3-thiophene-2-yl-isoxazole-5-yl)-ethanone (6.0 g, 31 mmol) obtainedin Preparation Example 5-10-a) in dichloromethane (30 mL) was addeddropwise diethylaminosulfur trifluoride (DAST) (16 mL, 0.12 mol) over 5min. at 0° C., and the suspension was warmed gradually to roomtemperature. After stirring at room temperature for 23 hours, theobtained solution was transferred to a separatory funnel and addeddropwise over 30 min to 4N aqueous sodium hydroxide solution (105 mL)cooled at 0° C. Then the obtained solution was warmed gradually to roomtemperature and filtrated through celite. The filtrate was separatedinto layers and extracted with chloroform (60 mL). Then the organiclayer was sequentially washed with saturated-aqueous sodium hydrogencarbonate solution (90 mL), 1N aqueous hydrochloric acid solution (60mL) and saturated aqueous sodium chloride solution (30 mL), and driedover magnesium sulfate. After filtration and evaporation, the obtainedresidue was separated and purified by silica gel chromatography(hexane:ethyl acetate=15:1) to give the title compound (6.2 g, 94%) as abrown oil.

c) 5-[5-(1,1-difluoroethyl)-isoxazol-3-yl]-thiophene-2-sulfonic acid

Under argon atmosphere, to a solution of5-(1,1-difluoroethyl)-3-thiophene-2-yl-isoxazole (6.2 g, 31 mmol)obtained in Preparation Example 5-10-b) in chloroform (100 mL) was addedchlorosulfonic acid (2.5 mL, 38 mmol), and the mixture was stirred atroom temperature for 3 days. The obtained solution was filtrated anddried under reduced pressure to give the title compound (7.9 g, yield93%) as a pale-brown powder.

d) 5-[5-(1,1-difluoroethyl)-isoxazol-3-yl]-thiophene-2-sulfonic acidchloride (step 5-10)

To a suspension of5-{5-(1,1-difluoroethyl)-isoxazol-3-yl}-thiophene-2-sulfonic acid (9.5g, 32 mmol) obtained in Preparation Example 5-10-c) in thionyl chloride(50 mL) was added dimethylformamide (1.0 mL) under argon atmosphere, andthe suspension was stirred at 80° C. for 16 hours. The obtained solutionwas concentrated, and chloroform (100 mL) was added. After azeotropicremoval of residual solvent with chloroform, chloroform (50 mL) wasadded to the residue. The obtained mixture was extracted twice,sequentially washed with water (20 mL) and saturated aqueous sodiumchloride solution (10 mL), and dried over magnesium sulfate. Afterfiltration and evaporation, the obtained residue was separated andpurified by silica gel chromatography (hexane:ethyl acetate=15:1) togive the title compound (6.9 g, 68%) as a yellow solid.

PREPARATION EXAMPLE 5-11(1S,2R,3R)-1-{5-[5-(1,1-difluoro-ethyl)-isoxazol-3-yl]-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylicacid t-butyl ester (step 5-11)

To a solution of(1S,2R,3R)-1-amino-2-methyl-3-phenyl-cyclopropanecarboxylic acid t-butylester (3.0 g, 12 mmol) obtained in Preparation Example 5-4 intetrahydrofuran (60 mL) were sequentially added5-{5-(1,1-difluoroethyl)-isoxazol-3-yl}-thiophene-2-sulfonic acidchloride (3.8 g, 12 mmol) obtained in Example 5-10 and 2,6-lutidine (3.1mL, 27 mmol) at room temperature under argon atmosphere. The obtainedsolution was warmed to 50° C., and stirred for 15 hours. Then, to theobtained solution was added saturated aqueous sodium chloride solution(60 mL), and the mixture was extracted twice with ethyl acetate (60 mL),sequentially washed with 2N aqueous hydrochloric acid solution (30 mL)and saturated aqueous sodium chloride solution (10 mL), and dried overmagnesium sulfate. After filtration and evaporation, the obtained crudeproduct was separated and purified by silica gel chromatography(hexane:ethyl acetate=10:1). The crude product was slurry-washed withhexane (60 mL) to give the title compound (3.8 g, 60%) as a pale-yellowsolid.

PREPARATION EXAMPLE 5-11-2(1R*,1aS*,8bS*)-1-{5-(4-chloro-phenyl)thiophene-2-sulfonylamino}-1,1a,2,3,4,8b-hexahydrobenzo[a]cyclopropa[c]cyclohepten-1-carboxylicacid ethyl ester (step 5-11)

To a solution of(1R*,1aS*,8bS*)-1-amino-1,1a,2,3,4,8b-hexahydrobenzo[a]cyclopropa[c]cyclohepten-1-carboxylicacid ethyl ester (0.22 g, 0.91 mmol) obtained in Preparation Example 4-1in pyridine (2.0 mL) was added 5-(4-chlorophenyl)-thiophene-2-sulfonylchloride (0.32 g, 1.1 mmol) at room temperature under argon atmosphere.After stirring for 4 hours, the mixture was concentrated under reducedpressure. The obtained residue was separated and purified by silica gelchromatography (hexane:ethyl acetate=10:1) to give the title compound(0.26 g, yield 56%) as a pale-yellow amorphous form.

PREPARATION EXAMPLE 5-11-3(1S,2R,3R)-2-methyl-1-{4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonylamino}-3-phenyl-cyclopropanecarboxylicacid t-butyl ester (step 5-11)

To a solution of chlorosulfonyl isocyanate (18 μL, 0.20 mmol) inacetonitrile (2 mL) was added 2-chloroethanol (14 μL, 0.20 mmol) at 0°C. The mixture was stirred at 0° C. for 30 min and then at roomtemperature for 1 hour. To this reaction mixture were addedN-methylmorpholine (89 μL, 0.81 mmol) and(1S,2R,3R)-1-amino-2-methyl-3-phenyl-cyclopropanecarboxylic acidtert-butyl ester (50 mg, 0.20 mmol). The reaction mixture was thenstirred at 50° C. for 3 hours. This crude solution was used directly inthe next step.

To the crude(1S,2R,2R)-2-methyl-1-(2-oxo-oxazolidine-3-sulfonylamino)-3-phenyl-cyclopropanecarboxylicacid tert-butyl ester (120 mg, 0.30 mmol) was added commerciallyavailable 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (70 mg, 0.30mmol) and the reaction mixture was heated at 80° C. for 30 min.N,N-dimethylacetamide (0.5 mL) was added to completely dissolvepiperazine. After heating for 24 hours, the reaction mixture was dilutedwith ethyl acetate and the organic layer was washed with saturatedsodium hydrogen carbonate solution and saturated sodium chloridesolution. After drying over magnesium sulfate, the solvent was removedin vacuo. The crude material was purified using prep TLC eluting with1:1 Hexanes/ethyl acetate (R_(f) 0.7) to afford the desired sulfamide ina 20% isolated yield.

PREPARATION EXAMPLE 5-11-45-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonicacid[(1R*,5R*,6R*)-2-oxo-6-phenyl-3-oxa-bicyclo[3.1.0]hexan-1-yl]-amide(step 5-11)

(1R*,5R*,6R*)-1-amino-6-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one (0.14 g,0.74 mmol) was dissolved in 3 mL of pyridine. After cooling to 0° C.,5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonyl chloride (0.31g, 0.96 mmol) was added in one portion. The reaction mixture was warmedto room temperature and stirred overnight. After concentration, thereaction mixture was diluted with EtOAc, washed with 10% citric acid,water (×2), 5% NaHCO₃ and brine and dried over Na₂SO₄. Afterconcentration, the crude product was purified by column chromatographyusing 2:1 hexanes/EtOAc to afford 0.26 g (75%) of the desired product.

PREPARATION EXAMPLE 5-11-5(1R*,2R*,3R*)-2-methoxymethyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylicacid methoxy-methyl-amide (step 5-11)

The(1R*,2R*,3R*)-1-amino-2-methoxymethyl-3-phenyl-cyclopropanecarboxylicacid methoxy-methyl-amide hydrochloride (22 mg, 0.082 mmol) wasdissolved in 1 mL of pyridine. To this solution was added5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonyl chloride (25mg, 0.079 mmol) and the mixture was stirred at room temperatureovernight. After concentration, the reaction mixture was diluted withEtOAc and washed with sat. NaHCO₃ (2×) and brine. After drying overMgSO₄, the solution was concentrated and purified using prep-TLC (1:1hexanes/EtOAc) to afford 13 mg of the desired product (32%).

PREPARATION EXAMPLE 6-1(1R*,2R*)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-hydroxymethyl-2-phenyl-cyclopropanecarboxylicacid t-butyl ester (step 6-1)

To a solution of(1R*,6R*)3-oxo-6-phenyl-4-oxa-2-aza-bicyclo[4.1.0]heptan-1-carboxylicacid t-butyl ester (5.0 g, 17 mmol) obtained in Preparation Example 2-5in tetrahydrofuran (50 mL) was sequentially added 15-crown-5 (0.34 mL,1.7 mmol) and sodium hydride (liquid paraffin 40% added, 1.7 g, 41 mmol)at 0° C. under nitrogen atmosphere. After stirring for 5 min., themixture was further stirred at room temperature for 30 min. The obtainedsolution was cooled to 0° C., and5-(4-chlorophenyl)-thiophene-2-sulfonyl chloride (6.1 g, 21 mmol) wasadded. After stirring at 0° C. for 15 min., the mixture was stirred atroom temperature for 6 hours. To the obtained solution were sequentiallyadded tetrahydrofuran (50 mL), methanol (100 mL) and 2N aqueous sodiumhydroxide solution (17 mL, 69 mmol). After stirring for 15 hours, themixture was concentrated to about half the amount under reducedpressure. To the obtained solution was added 5% aqueous potassiumhydrogen sulfate solution until the pH level read about 6. Then thesolution was extracted three times with ethyl acetate (50 mL), washedwith water (30 mL) and saturated aqueous sodium chloride solution (30mL), and dried over sodium sulfate. After filtration and evaporation,the obtained residue was purified by silica gel chromatography(hexane:ethyl acetate=7:3) to give the title compound (3.6 g, yield 40%)as a pale-yellow amorphous form.

PREPARATION EXAMPLE 6-2(1R*,2R*)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-2-(tetrahydro-pyran-2-yloxymethyl)-cyclopropanecarboxylicacid t-butyl ester (step 6-2)

To a solution of(1R*,2R*)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-hydroxymethyl-2-phenyl-cyclopropanecarboxylicacid-t-butyl ester (4.5 g, 8.7 mmol) obtained in Preparation Example 6-1in chloroform (45 mL) were sequentially added 3,4-dihydro-2H-pyran (2.0mL, 22 mmol) and p-toluenesulfonic acid monohydrate (0.17 g, 0.87 mmol)at room temperature under nitrogen atmosphere. After stirring for 1hour, saturated aqueous sodium hydrogen carbonate solution (40 mL) wasadded to the mixture. Then the aqueous layer was extracted three timeswith ethyl acetate (20 mL). The organic layer was washed with water (30mL) and saturated aqueous sodium chloride solution (30 mL), and driedover sodium sulfate. After filtration and evaporation, the obtainedresidue was purified by silica gel chromatography (hexane:ethylacetate=7:3) to give the title compound (4.9 g, yield 93%) as apale-yellow powder.

PREPARATION EXAMPLE 6-3(1R*,2R*)-1-[{(5-(4-chloro-phenyl)-thiophene-2-sulfonyl]-(2-trimethylsilanyl-ethyl)-amino}-2-phenyl-2-(tetrahydro-pyran-2-yloxymethyl)-cyclopropanecarboxylicacid t-butyl ester (step 6-3)

To a solution of(1R*,2R*)-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-2-(tetrahydro-pyran-2-yloxymethyl)-cyclopropanecarboxylicacid t-butyl ester (4.9 g, 8.0 mmol) obtained in Preparation Example6-2, triphenylphosphine (3.2 g, 12 mmol) and 2-trimethylsilylethanol(1.7 mL, 12 mmol) in tetrahydrofuran (49 mL) was dropwise addedazodicarboxylic acid diisopropyl ester (2.4 mL, 12 mmol) at roomtemperature under nitrogen atmosphere, and the mixture was stirred for15 hours. The obtained solution was purified by silica gelchromatography (hexane:ethyl acetate=4:1) to give the title compound(5.1 g, yield 91%) as a pale-yellow amorphous form.

PREPARATION EXAMPLE 6-4(1R*,2R*)-1-[{5-(4-chloro-phenyl)-thiophene-2-sulfonyl]-(2-trimethylsilanyl-ethyl)-amino}-2-hydroxymethyl-2-phenyl-cyclopropanecarboxylicacid t-butyl ester (step 6-4)

To a solution of(1R*,2R*)-1-{{5-(4-chloro-phenyl)-thiophene-2-sulfonyl}(2-trimethylsilanyl-ethyl)-amino}-2-phenyl-2-(tetrahydro-pyran-2-yloxymethyl)-cyclopropanecarboxylicacid t-butyl ester (5.1 g, 7.3 mmol) obtained in Preparation Example 6-3in methanol (50 mL) was added p-toluenesulfonic acid monohydrate (0.14g, 0.73 mmol) at room temperature under nitrogen atmosphere. Afterstirring for 1 hour, saturated aqueous sodium hydrogen carbonatesolution (10 mL) was added. The mixture was extracted three times withethyl acetate (20 mL). The organic layer was washed twice with water (30mL) and also washed twice with saturated aqueous sodium chloridesolution (30 mL), and dried over sodium sulfate. After filtration andevaporation, the obtained residue was purified by silica gelchromatography (hexane:ethyl acetate=7:3) to give the title compound 35(4.5 g, yield 99%) as a pale-yellow amorphous form.

PREPARATION EXAMPLE 6-5(1R*,2R*)-1-{[5-(4-chloro-phenyl)-thiophene-2-sulfonyl]-(2-trimethylsilanyl-ethyl)-amino]-2-methoxymethyl-2-phenyl-cyclopropanecarboxylicacid t-butyl-ester (step 6-5)

To a solution of(1R*,2R*)-1-{{5-(4-chloro-phenyl)-thiophene-2-sulfonyl}-(2-trimethylsilanyl-ethyl)-amino}-2-hydroxymethyl-2-phenyl-cyclopropanecarboxylicacid t-butyl ester (0.10 g, 0.16 mmol) obtained in Preparation Example6-4 in tetrahydrofuran (1.0 mL) were sequentially added methyl iodide(20 μL, 0.32 mmol) and sodium hydride (liquid paraffin 40% added, 13 mg,0.32 mmol) at 0° C. under nitrogen atmosphere. After stirring for 30min., the mixture was further stirred at room temperature for 26 hours.To the obtained solution were added 5% aqueous potassium hydrogensulfate solution (1.0 mL) and ethyl acetate (2.0 mL). The aqueous layerwas extracted three times with ethyl acetate (2.0 mL). The organic layerwas washed with water. (5.0 mL) and saturated aqueous sodium chloridesolution (5.0 mL), and dried over sodium sulfate. After filtration andevaporation, the obtained residue was purified by silica gelchromatography (hexane:ethyl acetate=7:3) to give the title compound (99mg, yield 98%) as a pale-yellow oil.

PREPARATION EXAMPLE 6-6(1R*,2S*)-1-{(5-bromo-thiophene-2-sulfonyl)-(2-trimethylsilanyl-ethyl)-amino}-2-methyl-2-phenyl-cyclopropanecarboxylicacid t-butyl ester (step 6-6)

To a solution of(1R*,2S*)-1-(5-bromo-thiophene-2-sulfonylamino)-2-methyl-2-phenyl-cyclopropanecarboxylicacid t-butyl ester (0.90 g, 1.9 mmol) obtained in a similar manner as inPreparation Example 5-5 in tetrahydrofuran (9.0 mL) were sequentiallyadded triphenylphosphine (0.75 g, 2.8 mmol), 2-trimethylsilylethanol(0.33 mL, 2.8 mmol) and azodicarboxylic acid diisopropyl ester (0.56 mL,2.8 mmol) under argon atmosphere, and the mixture was stirred at roomtemperature for 12 hours. After evaporation, the obtained residue wasseparated and purified by silica gel chromatography (hexane:ethylacetate=20:1) to give the title compound (0.90 g, yield 83%) as acolorless oil.

PREPARATION EXAMPLE 6-7(1S,2R)-1-(5-benzo[1,3]dioxo-5-yl-thiophene-2-sulfonylamino)-2-methyl-2-phenyl-cyclopropanecarboxylicacid t-butyl ester (step 6-7)

To a solution of(1S,2R)-1-(5-bromo-thiophene-2-sulfonylamino)-2-methyl-2-phenyl-cyclopropanecarboxylicacid t-butyl ester (52 mg, 0.11 mmol) obtained in a similar manner as inPreparation Example 5-5 in 1,2-dimethoxyethane (1.0 mL) weresequentially added 3,4-(methylenedioxy)phenylboronic acid (24 mg, 0.15mmol), potassium carbonate (46 mg, 0.33 mmol) and a catalytic amount oftetrakis(triphenylphosphine)palladium (0) under argon atmosphere. Afterstirring at 80° C. for 8 hours, the mixture was filtrated throughcelite. After evaporation, the obtained residue was separated andpurified by silica gel chromatography (hexane:ethyl acetate=10:1) togive the title compound (65 mg, purity 80%) as a colorless amorphousform.

PREPARATION EXAMPLE 6-7-2(1R*,2S*)-2-methyl-1-{(5-morpholin-4-yl-thiophene-2-sulfonyl)-(2-trimethylsilanyl-ethyl)-amino}-2-phenyl-cyclopropanecarboxylicacid t-butyl ester (step 6-7)

To a solution of(1R,2S)-1-[5-bromo-thiophene-2-sulfonyl)-(2-trimethylsilanyl-ethyl)-amino]-2-methyl-2-phenyl-cyclopropanecarboxylicacid t-butyl ester (52 mg, 91 μmol) obtained in Preparation Example 6-6in toluene (1.0 mL) were added sodium t-butoxide (26 mg, 0.27 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (13 mg, 27μmol), tris(dibenzylideneacetone)dipalladium (9.0 mg, 9.0 μmol) andmorpholine (40 μL, 0.46 mmol) under argon atmosphere, and the mixturewas stirred for 6 hours under refluxing. The obtained suspension wascooled to 0° C. and water (1.0 mL) was added. The mixture was extractedtwice with ethyl acetate (5.0 mL). The organic layer was sequentiallywashed with water (1.0 mL) and saturated aqueous sodium chloridesolution (1.0 mL), and dried over magnesium sulfate. After filtrationand evaporation, the obtained residue was separated and purified bysilica gel chromatography (hexane:ethyl acetate=10:1) to give the titlecompound (36 mg, yield 70%) as a white solid.

PREPARATION EXAMPLE 6-8(1R*,2S*)-2-methyl-1-(5-morpholin-4-yl-thiophene-2-sulfonylamino)-2-phenyl-cyclopropanecarboxylicacid t-butyl ester (step 6-8)

To(1R*,2S*)-2-methyl-1-{(5-morpholin-4-yl-thiophene-2-sulfonyl)-(2-trimethylsilanyl-ethyl)-amino}-2-phenyl-cyclopropanecarboxylicacid t-butyl ester (36 mg, 63 μmol) obtained in Preparation Example6-7-2 was added 1.0 M solution of tetrabutylammonium fluoride intetrahydrofuran (1.0 mL) under argon atmosphere, and the mixture wasstirred for 12 hours under refluxing. The obtained solution was cooledto 0° C. and water (1.0 mL) was added. The mixture was extracted twicewith ethyl acetate (5.0 mL). The organic layer was sequentially washedwith water (1.0 mL) and saturated aqueous sodium chloride solution (1.0mL), and dried over magnesium sulfate. After filtration and evaporation,the obtained residue was separated and purified by silica gelchromatography (hexane:ethyl acetate=3:1) to give the title compound (22mg, yield 73%) as a white solid.

PREPARATION EXAMPLE 6-9(1R*,2S*)-2-(3-amino-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylicacid t-butyl ester (step 6-9)

To a solution of(1R*,2S*)-2-(3-nitro-phenyl)-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylicacid t-butyl ester (0.46 g, 0.82 mmol) obtained in a similar manner asin Preparation Example 5-11 in a ethanol:chloroform=1:1 (5.0 mL) mixturewas added copper (II) acetate (0.23 g, 1.2 mmol), and the mixture wasstirred at room temperature for 5 min. to give a homogenous bluesolution. Then sodium borohydride (0.22 g, 5.8 mmol) was added slowly atroom temperature, and the mixture was stirred for 30 min. After theobtained solution was diluted with diethyl ether (5.0 mL) and ethylacetate (5.0 mL), the organic layer was sequentially washed withsaturated aqueous sodium hydrogen carbonate solution (10 mL) andsaturated aqueous sodium chloride solution (10 mL), and dried oversodium sulfate. After filtration and evaporation, the residue weregradually added ethyl acetate and hexane to allow precipitation ofcrystals. The crystals was filtrated to give the title compound (0.20 g,yield 46%) as a pale-yellow powder.

PREPARATION EXAMPLE 6-9-21-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-(isopropylamino-methyl)-2-phenyl-cyclopropanecarboxylicacid t-butyl ester (step 6-9)

To a solution of2-azidomethyl-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylicacid t-butyl ester (2.2 g, 4.0 mmol), which was produced in a similarmanner as in Preparation Example 5-11 from(1R*,2S*)-1-amino-2-azidomethyl-2-phenyl-cyclopropanecarboxylic acidt-butyl ester obtained in Preparation Example 5-4-2, in toluene (22 mL)was added triphenylphosphine (1.1 g, 4.2 mmol) under argon atmosphere,and the mixture was stirred at room temperature for 3 hours. To theobtained solution was added water (20 mL) and the mixture was stirred at100° C. for 1 hour. After evaporation, the obtained residue was purifiedby silica gel chromatography (chloroform:methanol=100:1 to 20:1) to give2-aminomethyl-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylicacid t-butyl ester (1.8 g, yield 86%).

To the obtained2-aminomethyl-1-{5-(4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-phenyl-cyclopropanecarboxylicacid t-butyl ester (60 mg, 0.12 mmol) in tetrahydrofuran (1.0 mL) wereadded acetone (13 μL, 0.17 mmol) and sodium triacetoxyborohydride (37mg, 0.17 mmol) at 0° C. under argon atmosphere, and the mixture wasstirred at room temperature for 20 hours. To the obtained solution wasadded acetic acid (50 μL), and the mixture was further stirred for 21hours. Then saturated aqueous sodium hydrogen carbonate solution (2.0mL) was added and the aqueous layer was extracted with ethyl acetate(3.0 mL). The organic layer was washed with water (2.0 mL) and saturatedaqueous sodium chloride solution (2.0 mL), and dried over magnesiumsulfate. After filtration and evaporation, the obtained residue waspurified by silica gel chromatography (chloroform:methanol=25:2) to givethe title compound (45 mg, yield 69%) as a pale-yellow oil.

PREPARATION EXAMPLE 6-10(1S,2R)-1-(6-methoxymethyl-imidazo[2,1-b]thiazol-2-sulfonylamino)-2-methyl-2-phenyl-cyclopropanecarboxylicacid methyl ester (step 6-10)

To a solution of(1S,2R)-1-(6-bromomethyl-imidazo[2,1-b]thiazol-2-sulfonylamino)-2-methyl-2-phenyl-cyclopropanecarboxylicacid methyl ester (32 mg, 65 μmol) obtained in Preparation Example 5-6in dimethylformamide (3.0 mL) were added methanol (0.60 mL) and asolution of 28% sodium methoxide in methanol (0.13 mL, 0.65 mmol) underargon atmosphere, and the mixture was stirred for 18 hours. To themixture was added saturated aqueous ammonium chloride solution (15 mL),and the aqueous layer was extracted with ethyl acetate (15 mL). Theorganic layer was washed with saturated aqueous sodium chloride solutionand dried over sodium sulfate. After filtration and evaporation, theobtained residue was separated and purified by silica gel chromatography(hexane:ethyl acetate=1:2) to give the title compound (25 mg, yield 88%)as a white solid.

PREPARATION EXAMPLE 6-11(1R*,2R*,3R*)-2-methoxymethyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylicacid (step 6-11)

(1R*,2R*,3R*)-2-methoxymethyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylicacid methoxy-methyl-amide (55 mg, 0.10 mmol) was dissolved in 6 mL ofdichloromethane. Diisobutylaluminum hydride (1M, 0.22 mL, 0.22 mmol) wasadded dropwise at −78° C. This mixture was monitored by LC/MS andsupplemental diisobutylaluminum hydride was repeatedly added until thereaction was completed. After quenching with methanol, the reactionmixture was partitioned between dichloromethane and 1N HCl. The organiclayer was washed with brine, dried over MgSO₄ and concentrated. Thecrude product was used directly in the next step.

The crude mixture (assumed 0.1 mmol) was dissolved in 12 mL of 3:1acetone/water. To this solution were added NaClO₂ (31 mg, 0.34 mmol, 3.4equiv), NaH₂PO₄ (12 mg, 0.10 mmol, 1.0 equiv) and 2-methyl-2-butene (fewdrops). After stirring at room temperature for 4 hours, the reactionmixture was concentrated and partitioned between EtOAc and water. Theaqueous solution was further extracted with EtOAc (×2). The combinedorganic layers were dried over MgSO₄ and concentrated to give a yellowoil. This material was given to our purification group to purify andquite a lot of material was lost during repeated purifications. Furtherpurification using prep TLC afforded the product (2 mg) in a 50% purity.

EXAMPLE 1S,2R)-1-(4′-Chlorobiphenyl-4-sulfonylamino)-2-phenylcyclopropanecarboxylicacid a) (1S,2R)-1-Amino-2-phenylcyclopropanecarboxylic acid

To commercially available(1R,2S)-1-tert-butoxycarbonylamino-2-phenylcyclopropanecarboxylic acid(130 mg, 0.45 mmol) was added 4N hydrochloric acid-1,4-dioxane solution(2.0 mL, 16 v/w) and the mixture was stirred for 1 hr at roomtemperature. Diethyl ether (1.0 mL) was added thereto and the mixturewas stirred for 5 min, after which the resulting crystals were collectedby filtration. The crystals were washed with diethyl ether (1.0 mL) anddried under reduced pressure to give the title compound (81 mg, whitepowder, yield 84%).

¹H-NMR (DMSO, 300 MHz): 1.84 (dd, J=6.0, 9.0 Hz, 1H), 2.03 (dd, J=6.0,9.0 Hz, 1H), 2.99 (t, J=10.5 Hz, 1H), 7.20-7.40 (m, 5H), 8.29 (br, 3H)

b)(1S,2R)-1-(4′-Chlorobiphenyl-4-sulfonylamino)-2-phenylcyclopropanecarboxylicacid

To a suspension of (1S,2R)-1-amino-2-phenylcyclopropanecarboxylic acid(80 mg, 0.38 mol) obtained in Example 1-a) in 1,4-dioxane:water=1:1 (3.2mL, 40 v/w) were successively added triethylamine (0.18 mL, 1.3 mmol),4-chlorobiphenylsulfonic acid chloride (110 mg, 1.1 mol) andN,N-dimethylaminopyridine (9.0 mg, 0.20 mmol) at 0° C. The mixture wasstirred for 12 hr at room temperature, and 1N hydrochloric acid wasadded thereto until its pH reached approximately 1. The organic layerwas extracted twice with ethyl acetate (4.0 mL) and concentrated. Then,the obtained crude product was separated and purified by thin-layersilica gel chromatography (chloroform:methanol=7:1) to give the titlecompound (60 mg, white amorphous solid, 37%).

EXAMPLE 1-21-[4-(2,4-Dichlorobenzyloxy)benzenesulfonylamino]-2-phenylcyclopropanecarboxylicacid hydroxyamide

Under an argon atmosphere of,1-{4-(2,4-dichlorobenzyloxy)benzenesulfonylamino}-2-phenylcyclopropanecarboxylicacid (120 mg, 0.24 mmol) obtained in the same manner as in Example 1 wasdissolved in tetrahydrofuran (1.2 mL, 10 v/w) and a methylene chloridesolution of 2N oxalyl chloride (0.13 mL, 0.26 mmol) and a catalyticamount of N,N-dimethylformamide were added dropwise thereto at −20° C.After warming to 0° C. over 1 hr, O-(trimethylsilyl)hydroxylamino (0.064mL, 0.52 mmol) and N-methylmorpholine (0.052 mL, 0.48 mmol) weresuccessively added dropwise thereto. The mixture was stirred at 0° C.for 1.5 hr, and 1N-hydrochloric acid (1.0 mL) and water (5.0 mL) wereadded thereto. The mixture was extracted twice with ethyl acetate (5.0mL). The organic layer was successively washed with water (5.0 mL) andsaturated brine (5.0 mL), and dried over magnesium sulfate (1.0 g).After filtration, the solvent was evaporated off under reduced pressure,and the obtained crude product was purified by silica gel chromatography(chloroform:methanol=10:1). The solvent was evaporated off, and diethylether was added to the obtained colorless oil. The mixture was stirredfor 10 min at room temperature and the precipitated crystals werecollected by filtration and dried under reduced pressure to give thetitle compound (88 mg, yield 73%) as a white solid.

Melting point 164.0-169.0° C.

EXAMPLES 1-3 TO 1-149

In the same manner as in Examples 1 and 1-2, the compounds of Examples1-3 to 1-149 were obtained.

The structural formulas of the compounds of Examples 1 to 1-149 areshown in Tables 1-1 to 1-30.

EXAMPLE 24-{5-((1S,2R)-1-carboxy-2-phenyl-cyclopropanesulfamoyl)-thiophene-2-yl}-3,6-dihydro-2H-pyridin-1-carboxylicacid t-butyl ester (step 5-8)

The title compound (0.11 g, yield 90%) was obtained in a similar manneras in Preparation Example 5-1 from4-{5-[(1S,2R)-1-methoxycarbonyl-2-phenyl-cyclopropylsulfamyl]-thiophen-2-yl}-3,6-dihydro-2H-pyridin-1-carboxylicacid t-butyl ester (0.13 g, 0.24 mmol).

EXAMPLE 2-2(1S,2R)-2-phenyl-1-{5-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylicacid hydrochloride (step 5-9)

To a solution of4-{5-((1S,2R)-1-carboxy-2-phenyl-cyclopropanesulfamoyl)-thiophen-2-yl}-3,6-dihydro-2H-pyridin-1-carboxylicacid t-butyl ester (0.11 g, 0.22 mmol) obtained in Example 2 in methanol(0.86 mL) was added 4N hydrochloric acid dioxane solution (2.2 mL) underargon atmosphere, and the mixture was stirred at room temperature for 1hour. The title compound (0.11 g, yield 100%) was obtained byevaporation under reduced pressure.

EXAMPLE 2-34-{5-((1S,2R)-1-carboxy-2-phenyl-cyclopropanesulfamoyl)-thiophene-2-yl}-3,6-dihydro-2H-pyridin-1-carboxylicacid methyl ester (step 5-9)

To a solution of(1S,2R)-2-phenyl-1-{5-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylicacid hydrochloride (30 mg, 69 μmol) obtained in Example 2-2 inchloroform (0.60 mL) were added triethylamine (39 μL, 0.28 mmol) andmethyl chlorocarbonate (6.4 μL, 83 μmol) under argon atmosphere, and themixture was stirred at room temperature for 18 hours. Saturated aqueousammonium chloride solution, a small amount of ethyl acetate anddiisopropyl ether were added to the mixture to allow precipitation ofcrystal, and the obtained crystals were filtrated to give the titlecompound (13 mg, yield 42%).

EXAMPLE 2-4(1S,2R,3R)-1-{5-(4-ethynyl-pyrazole-1-yl)-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylicacid (step 5-9)

To a solution of a deprotected compound of(1S,2R,3R)-1-[5-(4-iodo-pyrazol-1-yl)-thiophene-2-sulfonylamino-2-methyl-3-phenyl-cyclopropanecarboxylicacid t-butyl ester (0.10 g, 0.19 mmol) obtained in Preparation Example5-7 in chloroform (1.0 mL) were sequentially added triethylamine (0.13mL, 0.94 mmol), trimethylsilylacetylene (54 μL, 0.38 mmol), copperiodide (I) (1.8 mg, 9.4 μmol) anddichlorobis(triphenylphosphine)palladium (II) (6.6 mg, 9.4 μmol) at roomtemperature under nitrogen atmosphere. After stirring for 1 hour withoutany modification, 5% aqueous potassium hydrogen sulfate solution (1 mL)was added to the mixture. The aqueous layer was extracted three timeswith ethyl-acetate (2 mL). The organic layer was washed with water (3mL) and saturated aqueous sodium chloride solution (3 mL), and driedover sodium sulfate. After filtration and evaporation, the obtainedcrude product was purified by silica gel chromatography (hexane:ethylacetate=1:1) to give(1S,2R,3R)-2-methyl-3-phenyl-1-{5-(4-trimethylsilanylethynyl-pyrazol-1-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylicacid (75 mg, yield 79%) as a brown oil.

To a solution of(1S,2R,3R)-2-methyl-3-phenyl-1-{5-(4-trimethylsilanylethynyl-pyrazol-1-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylicacid (66 mg, 0.13 mmol) in methanol (1.0 mL) was added potassiumcarbonate (36 mg, 0.26 mmol) at room temperature. After stirring for 1hour without any modification, to the mixture was added 5% aqueouspotassium hydrogen sulfate solution (3.0 mL). The aqueous layer wasextracted three times with ethyl acetate (2.0 mL). The organic layer waswashed with water (3.0 mL) and saturated aqueous sodium chloridesolution (3.0 mL), and dried over sodium sulfate. After filtration andevaporation of the residue, chloroform (1.0 mL) was added to theobtained residue to allow precipitation of crystals. Afterslurry-washing and filtration, the residue was dried under reducedpressure to give the title compound (54 mg, yield 98%) as a pale-yellowpowder.

EXAMPLE 2-5(1S,2R,3R)-2-methyl-3-phenyl-1-{4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonylamino}-cyclopropanecarboxylicacid (step 6-11)

To a solution of(1S,2R,3R)-2-methyl-3-phenyl-1-{4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonylamino}-cyclopropanecarboxylicacid t-butyl ester (33 mg, 0.061 mmol) obtained in Preparation Example5-11-3 in dichloromethane (1.5 mL) was added trifuluoroacetic acid (1.5mL). The reaction mixture was stirred at room temperature for 3 hours.The excess trifuluoroacetic acid was removed by azeotropic distillation(twice) with toluene. Toluene was removed by azeotroping twice withdichloromethane and drying under hivac. The material was purified byprep TLC eluting with 9:1 chloroform/methanol (Rf 0.3). The product wasfurther purified by dissolving in a small amount of dichloromethane andadding hexane to allow precipitation of the product as a white solid(88% yield).

EXAMPLE 2-6(1S,2R)-2-methyl-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylicacid (step 6-11)

To a solution of(1S,2R)-2-methyl-2-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylicacid t-butyl ester (5.0 g, 9.4 mmol) obtained in a similar manner as inPreparation Example 5-11 in chloroform (50 mL) was added trifluoroaceticacid (25 mL), and the mixture was stirred at room temperature for 21hours. The solvent was evaporated under reduced pressure. Afterazeotropic removal of residual solvent with methanol, the residue wasdissolved in a small amount of methanol. To the mixture was added waterat 0° C. to allow precipitation of crystals. The crystals were filtratedand dried to give the title compound (4.3 g, yield 97%, [α]²⁵ _(D)+72.6° (c 1.00, MeOH), m.p. 130-132° C.) as a white amorphous form.

EXAMPLE 2-7(1S,2R,3R)-2-methyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylicacid (step 6-11)

(1S,2R,3R)-2-methyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylicacid t-butyl ester (7.2 g, 14 mmol) obtained in a similar manner as inPreparation Example 5-11 was deprotected in a similar manner as inExample 2-6 to give the title compound {5.9 g, yield 90%, [α]²⁵ _(D)+81.0° (c 1.10, MeOH)} as white crystals.

EXAMPLE 2-8(1R*,1aS*,8bS*)-1-{5-(4-chloro-phenyl)thiophene-2-sulfonylamino}-1,1a,2,3,4,8b-hexahydrobenzo[a]cyclopropane[c]cyclohepten-1-carboxylicacid (step 6-11)

To a solution of(1R*,1aS*,8bS*)-1-{5-(4-chloro-phenyl)thiophene-2-sulfonylamino}-1,1a,2,3,4,8b-hexahydrobenzo[a]cyclopropane[c]cyclohepten-1-carboxylicacid ethyl ester (0.25 g, 0.50 mmol) obtained in Preparation Example5-11-2 in a methanol:tetrahydrofuran=1:1 (5.0 mL) mixture was added 4Naqueous sodium hydroxide solution (1.0 mL, 4.0 mmol), and the mixturewas refluxed for 5 days. After putting back to room temperature, ethylacetate (5.0 mL) and 1N aqueous hydrochloric acid solution (5.0 mL) weresequentially added to the mixture. After separating into layers, theaqueous layer was extracted twice with ethyl acetate (100 mL), and driedover magnesium sulfate. After filtration and evaporation, the residuewas separated and purified by silica gel chromatography (hexane:ethylacetate=1:1) to give the title compound (0.15 g, yield 65%) as a whiteamorphous form.

EXAMPLE 2-9(1S,2R,3R)-1-{5-[5-(1,1-difluoro-ethyl)-isoxazol-3-yl]-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylicacid (step 6-11)

To a solution of(1S,2R,3R)-1-{5-{5-(1,1-difluoro-ethyl)-isoxazol-3-yl}-thiophene-2-sulfonylamino}-2-methyl-3-phenyl-cyclopropanecarboxylicacid t-butyl ester (4.1 g, 7.8 mmol) obtained in Preparation Example5-11 in chloroform (40 mL) was added trifluoroacetic acid (20 mL), andthe mixture was stirred at room temperature for 20 hours. Then themixture was evaporated under reduced pressure. The residue wasazeotroped with a mixed solvent of chloroform and hexane, and dissolvedin methanol (30 mL). After treatment with activated carbon (1 g), thesolvent was evaporated and the residue was dissolved in methanol (30mL). To the obtained solution was added water at 0° C. to allowprecipitation of crystals. The crystals were filtrated and dried to givethe title compound {3.3 g, yield 90%, [α]²⁵ _(D) +83.6° (c 0.45, MeOH),m.p. 177-178° C.} as white crystals.

EXAMPLE 2-10(1R*,2R*,3R*)-2-hydroxymethyl-3-phenyl-1-{5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino}-cyclopropanecarboxylicacid (step 5-12)

To 5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonic acid{(1R*,5R*,6R*)-2-oxo-6-phenyl-3-oxa-bicyclo[3.1.0]hex-1-yl}-amide (53mg, 11 mmol) were added LiOH—H₂O (11 mg, 0.27 mmol), 1 mL of THF and 0.5mL of water. After stirring overnight at room temperature, the reactionmixture was concentrated, diluted with water (2 mL), and acidified to pH4 with 2N KHSO₄. The product was extracted with EtOAc, washed with water(×2), brine and dried over Na₂SO₄. After concentrating, the product wasprecipitated from dichloromethane/hexane to afford the desired productas a white solid (46 mg, 86% yield).

EXAMPLE 2-11(1S,2R,3R)-2-methyl-3-phenyl-1-(4-phenylcarbamoyl-piperazine-1-sulfamoylamino)-cyclopropanecarboxylicacid (step 5-13)

4-((1S,2R,3R)-1-t-butoxycarbonyl-2-methyl-3-phenyl-cyclopropylsulfamoyl)-piperazine-1-carboxylicacid t-butyl ester (0.24 g, 0.48 mmol) obtained in Preparation Example5-5-2, dioxane (0.20 mL) and 4N hydrochloric acid in dioxane (2.0 mL)were mixed, and the mixture was stirred at room temperature for 16hours. After the obtained solution was concentrated, the residue wasslurry-washed with ethyl acetate (5.0 mL) to give(1S,2R,3R)-2-methyl-3-phenyl-1-(piperazine-1-sulfamoylamino)-cyclopropanecarboxylicacid (0.15 g, yield 84%) as a white solid.

To a solution of the obtained(1S,2R,3R)-2-methyl-3-phenyl-1-(piperazine-1-sulfamoylamino)-cyclopropanecarboxylicacid (20 mg, 53 μmol) in tetrahydrofuran (1.0 mL) were addedtriethylamine (11 μL, 80 μmol) and phenyl isocyanate (8.7 μL, 80 μmol)at 0° C., and the mixture was stirred for 3 hours. To the obtainedsolution was added 10% aqueous potassium hydrogen sulfate solution (1.0mL), and the aqueous layer was extracted twice with ethyl acetate (2.0mL). After the organic layer was concentrated, the residue was purifiedby silica gel chromatography (chloroform:methanol=10:1) to give thetitle compound (20 mg, yield 80%) as a colorless amorphous form.

EXAMPLE 2-12(1S,2R)-1-{5-(3-amino-4-chloro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylicacid (step 5-14)

To a solution of(1S,2R)-1-{5-(4-chloro-3-nitro-phenyl)-thiophene-2-sulfonylamino}-2-methyl-2-phenyl-cyclopropanecarboxylicacid t-butyl ester (23 mg, 41 μmol), which was obtained from(1S,2R,3R)-1-amino-2-methyl-3-phenyl-cyclopropanecarboxylic acid t-butylester obtained in Preparation Example 5-4 by the general method of steps5-5 and 5-6, in ethanol (0.30 mL) was added tin dichloride dihydrate (37mg, 0.16 mmol), and the mixture was stirred at 100° C. for 2 hours. Tothe obtained solution were added saturated aqueous sodium hydrogencarbonate solution (1.0 mL) and methanol (1.0 mL), and the mixture wasfiltrated. The eluent was evaporated and the residue was separated andpurified by silica gel chromatography (chloroform:methanol=9:1) to givethe title compound (8.3 mg, yield 43%) as a white amorphous form.

EXAMPLE 2-13(1R*,1aS*,6aS*)-1-[4-(2,4-dichloro-benzyloxy)-benzenesulfonylamino]-1,1a,6,6a-tetrahydro-cyclopropa[a]inden-1-carboxylicacid hydroxyamide (step 5-15)

After(1R*,1aS*,6aS*)-1-[4-(2,4-dichloro-benzyloxy)-benzenesulfonylamino]-1,1a,6,6a-tetrahydro-cyclopropane[a]inden-1-carboxylicacid (92 mg, 0.18 mmol) obtained in a similar manner as in PreparationExample 6-11 was azeotroped with toluene, the residue was dissolved intetrahydrofuran (2.0 mL). Under argon atmosphere, 2 M oxalyl chloridedichloromethane solution (0.12 mL, 0.24 mmol) and a catalytic amount ofN,N-dimethylformamide were sequentially added dropwise at −20° C. Afterstirring at 0° C. for 1 hour, O-(trimethylsilyl)hydroxylamine (59 μL,0.48 mmol) and N-methylmorpholin (40 μL, 0.36 mmol) were sequentiallyadded dropwise at −20° C. After stirring at 0° C. for 1 hour, 1N aqueoushydrochloric acid solution (1.0 mL) was added, and the mixture wasextracted twice with ethyl acetate (20 mL). The organic layer was washedwith water (3.0 mL) and dried over magnesium sulfate. After filtrationand evaporation, the obtained residue was purified by silica gelchromatography (hexane:ethyl acetate=1:1). Further, diisopropyl etherwas added to the obtained residue to allow precipitation. Afterfiltration, a white solid (43 mg, yield 46%) was obtained under reducedpressure.

EXAMPLE 2-14 TO 2-625

The compounds of Examples 2-14 to 2-625 were produced from the compoundsobtained in Preparation Examples or by known preparation methods andusing similar methods of Examples 1, 1-2, 2-1 to 2-13.

The structural formulas of the compounds of Examples 2 to 2-625 areshown in Tables 2-1 to 2-125.

TABLE 1-1 Example Structural formula NMR 1

(DMSO-d6-300)1.50 (dd, J = 6.0, 9.0 Hz, 1 H),1.88-1.97 (m, 1 H),2.57-2.66 (m,1 H), 7.12-7.26 (m, 5 H),7.57 (dd, J = 3.0, 6.0 Hz, 2H),7.78 (dd, J = 3.0, 6.0 Hz, 2 H),7.85 (br, 4 H) 1-2

(DMSO-d6-300)1.01-1.10 (m, 1 H), 1.90 (dd,J = 6.0, 9.0 Hz, 1 H),2.40-2.52 (m, 1 H), 5.24 (s, 2 H),7.07-7.24 (m, 7 H), 7.49 (dd,J = 3.0,9.0 Hz, 1 H), 7.65 (d,J = 9.0 Hz, 1 H), 7.72 (d, J = 3.0 Hz,1 H), 7.76(d, J = 6.0 Hz, 2 H),8.50 (brs, 2 H), 10.20 (brs, 1 H) 1-3

(DMSO-d6-300)1.45 (dd, J = 9.8, 4.8 Hz, 1 H),1.73 (dd, J = 8.2, 5.2 Hz,1 H),2.37 (t, J = 9.20 Hz, 1 H), 4.21 (d,J = 5.5 Hz, 2 H), 6.00-6.09(m,1 H), 6.29-6.50 (m, 3 H), 6.85 (t,J = 7.7 Hz, 1 H), 7.32 (dd, J =7.9,4.9 Hz, 1 H), 7.53-7.60 (m, 2 H),7.68-7.80 (m, 3 H), 7.85 (s, 4H),8.42 (dd, J = 4.8, 1.8 Hz, 1 H),8.55 (d, J = 1.8 Hz, 1 H) 1-4

(DMSO-d6-300)0.84 (dd, J = 3.0, 9.0 Hz, 1 H),0.97 (dd, J = 6.0, 9.0 Hz,1 H),2.58 (t, J = 9.0 Hz, 1 H), 3.75 (s,3 H), 6.81 (t, J = 7.5 Hz, 1H),6.89 (brd, J = 9.0 Hz, 1 H),7.03 (brd, J = 9.0 Hz, 1 H),7.17 (t, J =9.0 Hz, 1 H),7.53 (brd, J = 9.0 Hz, 2 H),7.56 (d, J = 3.0 Hz, 1 H), 7.58(d,J = 3.0 Hz, 1 H), 7.76 (brd,J = 9.0 Hz, 2 H), 9.01 (br, 1 H),11.98(br, 1 H) 1-5

(DMSO-d6-300)1.79-1.87 (m, 1 H), 1.96-2.03 (m,1 H), 2.53-2.58 (m, 1 H),7.10-7.16 (m, 2 H), 7.20-7.28 (m, 3 H),7.58 (d, J = 9.0 Hz, 2 H),7.74-7.86 (m, 6 H)

TABLE 1-2 Example Structural formula NMR 1-6

(DMSO-d6-300)1.79-1.87 (m, 1 H), 1.96-2.03 (m,1 H), 2.53-2.58 (m, 1 H),7.10-7.16 (m, 2 H), 7.20-7.28 (m, 3 H),7.58 (d, J = 9.0 Hz, 2 H),7.74-7.86 (m, 6 H) 1-7

(DMSO-d6-300)1.50 (dd, J = 6.0, 9.0 Hz, 1 H),1.88-1.97 (m, 1 H),2.57-2.66 (m,1H), 7.12-7.26 (m, 5 H),7.57 (dd, J = 3.0, 6.0 Hz, 2H),7.78 (dd, J = 3.0, 6.0 Hz, 2 H),7.85 (br, 4 H) 1-8

(DMSO-d6-300)1.18-1.26 (m, 1 H), 1.31-1.41 (m,1 H), 1.58-1.71 (m, 1 H),2.69-2.78 (m, 2 H), 7.13-7.32 (m,5 H), 7.58 (brd, J = 9.0 Hz,2 H),7.74-7.81 (m, 4 H), 7.85 (brd,J = 9.0 Hz, 2 H) 1-9

(DMSO-d6-300)0.60 (dd, J = 3.0, 9.0 Hz, 1 H),0.67 (dd, J = 3.0, 6.0 Hz,1 H),0.82 (dd, J = 6.0, 9.0 Hz, 1 H),2.73 (t, J = 7.5 Hz, 2 H),7.16-7.32 (m, 5 H), 7.58 (d, J = 9.0 Hz,2 H), 7.78 (d, J = 9.0 Hz, 4H),7.86 (d, J = 9.0 Hz, 2 H) 1-10

(CDCL3-400)1.81-1.93 (m, 1 H), 1.96-2.05 (m,1 H), 2.81 (t, J = 8.0 Hz, 1H),5.84 (brs, 1 H), 6.76-6.85 (m,2 H), 6.87-6.94 (m, 3 H), 7.07 (t,J =8.0 Hz, 1 H), 7.14 (t, J = 8.0 Hz,1 H), 7.28 (d, J = 8.0 Hz, 2 H),7.43(d, J = 8.0 Hz, 2 H), 7.50 (d,J = 8.0 Hz, 2 H), 7.61 (d, J = 8.0 Hz,2H), 7.88 (d, J = 8.0 Hz, 2 H)

TABLE 1-3 Example Structural formula NMR 1-11

(DMSO-d6-300)1.48-1.56 (m, 1 H), 1.84-1.93 (m,1 H), 2.56-2.65 (m, 1H),6.81 (br, 2 H), 6.95 (d, J = 9.0 Hz,2 H), 6.97-7.03 (m, 1 H), 7.25(t,J = 9.0 Hz, 1 H), 7.39 (d, J = 9.0 Hz,2 H), 7.57 (dd, J = 3.0, 9.0Hz,2 H), 7.77 (dd, J = 3.0, 9.0 Hz,2 H), 7.83 (br, 4 H), 7.89 (d,J = 3.0Hz, 1 H) 1-12

(DMSO-d6-300)1.45 (dd, J = 6.0, 12.0 Hz, 1 H),1.93 (dd, J = 6.0, 9.0 Hz,1 H),2.64 (t, J = 10.5 Hz, 1 H), 3.69 (s,3 H), 6.72-6.81 (m, 3 H), 7.15(t,J = 7.5 Hz, 1 H), 7.57 (d, J = 9.0 Hz,2 H), 7.78 (d, J = 9.0 Hz, 2H),7.83-7.91 (m, 4 H) 1-13

(DMSO-d6-300)1.50-1.62 (m, 1 H), 1.79-1.92 (m,1 H), 2.42-2.55 (m, 1 H),3.74 (s,3 H), 6.78 (t, J = 7.5 Hz, 1 H),6.87 (d, J = 9.0 Hz, 1 H), 6.99(d,J = 9.0 Hz, 1 H), 7.14 (t, J = 7.5 Hz,1 H), 7.57 (d, J = 9.0 Hz, 2H),7.78 (d, J = 9.0 Hz, 2 H), 7.87 (s,4 H) 1-14

(DMSO-d6-300)1.49 (dd, J = 5.7, 9.4 Hz, 1 H),1.97 (dd, J = 5.7, 8.7 Hz,1 H),2.59 (dd, J = 8.7, 9.4 Hz, 1 H),6.69 (d, J = 7.9 Hz, 1 H),6.94-7.04 (m, 3 H), 7.09-7.22 (m, 3 H),7.38 (dd, J = 7.5, 8.3 Hz, 2H),7.57 (d, J = 8.7 Hz, 2 H), 7.77 (d,J = 8.83 Hz, 2 H), 7.85 (s, 4H),8.83 (s, 1 H), 12.20 (s, 1 H). 1-15

(DMSO-d6-300)1.43 (dd, J = 5.7, 9.4 Hz, 1 H),1.92 (dd, J = 5.7, 8.7 Hz,1 H),2.61 (dd, J = 8.7, 9.4 Hz, 1 H),3.69 (s, 3 H), 6.81 (d, J = 8.7Hz,2 H), 7.12 (d, J = 8.7 Hz, 2 H),7.57 (d, J = 8.3 Hz, 2 H), 7.78 (d,J= 8.6 Hz, 2 H), 7.87 (s, 4 H),8.90 (s, 4 H), 12.05 (s, 4 H).

TABLE 1-4 Example Structural formula NMR 1-16

(DMSO-d6-300)1.50 (dd, J = 6.0, 9.0 Hz, 1 H),1.92 (dd, J = 6.0, 9.0 Hz,1 H),2.57-2.67 (m, 1 H), 6.87 (d,J = 9.0 Hz, 2 H), 6.94 (d, J = 9.0 Hz,2H), 7.12 (t, J = 7.5 Hz, 1 H),7.20 (d, J = 9.0 Hz, 2 H), 7.31-7.41 (m, 2H), 7.57 (d, J = 9.0 Hz,2 H), 7.78 (d, J = 9.0 Hz, 2 H),7.87 (s, 4 H)1-17

(CDCL3-300)2.08-2.20 (m, 2 H), 3.01 (t,J = 9.0 Hz, 1 H), 5.79 (brs, 1H),7.39-7.59 (m, 3 H), 7.69 (d,J = 9.0 Hz, 2 H), 7.96 (d, J = 9.0 Hz,2H), 8.03-8.11 (m, 2 H) 1-18

(DMSO-d6-300)1.37 (dd, J = 6.0, 12.0 Hz, 1 H),1.81 (dd, J = 3.0, 9.0 Hz,1 H),2.45-2.54 (m, 1 H), 4.93 (brs,1 H), 6.32-6.45 (m, 3 H), 6.85 (t,J =7.5 Hz, 1 H), 7.57 (d, J = 9.0 Hz,2 H), 7.78 (d, J = 9.0 Hz, 2H),7.74-7.90 (m, 4 H), 8.92 (brs,1 H) 1-19

(DMSO-d6-300)1.04-1.84 (m, 8 H), 2.60-2.95 (m,2 H), 3.15-3.28 (m, 2 H),7.58 (d,J = 9.0 Hz, 2 H), 7.74-7.91 (m,6 H), 8.36-8.87 (m, 3 H),12.60(brs, 1 H) 1-20

(DMSO-d6-300)0.93 (d, J = 6.0 Hz, 6 H), 1.55 (dd,J = 6.0, 9.0 Hz, 1 H),1.76 (dd,J = 6.0, 9.0 Hz, 1 H), 1.88-1.99 (m, 1 H), 2.41 (t, J = 9.0Hz,1 H), 3.61 (d, J = 6.0 Hz, 2 H),6.62-6.70 (m, 3 H), 7.04 (t,J = 7.5Hz, 1 H), 7.57 (d, J = 9.0 Hz,2 H), 7.77 (d, J = 9.0 Hz, 2 H),7.84 (d, J= 9.0 Hz, 2 H), 7.87 (d,J = 9.0 Hz, 2 H)

TABLE 1-5 Example Structural formula NMR 1-21

(DMSO-d6-300)1.42 (dd, J = 3.0, 9.0 Hz, 1 H),1.90 (dd, J = 6.0, 9.0 Hz,1 H),2.61 (t, J = 9.0 Hz, 1 H), 2.83 (s,6 H), 6.47-6.58 (m, 3 H), 7.03(t,J = 7.5 Hz, 1 H), 7.57 (d, J = 9.0 Hz,2 H), 7.78 (d, J = 9.0 Hz, 2H),7.82-7.91 (m, 4 H), 8.91 (brs,1 H), 12.05 (brs, 1 H) 1-22

(DMSO-d6-300)1.58 (dd, J = 6.0, 9.0 Hz, 1 H),2.07 (dd, J = 6.0, 9.0 Hz,1 H),2.81 (t, J = 9.0 Hz, 1 H), 7.48-7.60 (m, 4 H), 7.57 (d, J = 9.0Hz,2 H), 7.78 (d, J = 9.0 Hz, 2 H),7.87 (s, 4 H), 8.96 (brs, 1 H),12.26(brs, 1 H) 1-23

(DMSO-d6-300)1.52 (dd, J = 5.7, 9.8 Hz, 1 H),2.00 (dd, J = 5.7, 8.7 Hz,1 H),2.71 (dd, J = 8.7, 9.8 Hz, 1 H),7.19-7.26 (m, 2 H), 7.35-7.41 (m,2H), 7.57 (d, J = 8.3 Hz, 2 H),7.78 (d, J = 8.7 Hz, 2 H), 7.87 (s,4 H),8.93 (s, 1 H), 12.27 (s,1 H). 1-24

(DMSO-d6-300)0.92 (d, J = 6.8 Hz, 6 H), 1.47 (dd,J = 5.3, 9.4 Hz, 1 H),1.90 (dd,J = 5.3, 8.7 Hz, 1 H), 2.00-2.12 (m, 1 H), 2.16 (d, J = 6.8Hz,2 H), 2.66 (dd, J = 8.7, 9.4 Hz,1 H), 6.86 (d, J = 7.2 Hz, 1 H),7.14(dd, J = 7.5, 8.3 Hz, 1 H),7.44 (d, J = 8.3 Hz, 1 H), 7.47 (d,1 H), 7.57(d, J = 8.7 Hz, 2 H),7.78 (d, J = 8.7 Hz, 2 H), 7.87 (s,4 H), 8.96 (s, 1H), 9.78 (s, 1 H),12.12 (s, 1 H). 1-25

(DMSO-d6-300)1.46 (dd, J = 5.7, 9.4 Hz, 1 H),1.88 (dd, J = 5.7, 8.7 Hz,1 H),2.65 (dd, J = 8.7, 9.4 Hz, 1 H),6.43 (s, 1 H), 6.64 (s, 2 H),6.99(d, J = 7.5 Hz, 4 H), 7.14 (t,J = 7.5 Hz, 2 H), 7.38 (t, J = 7.5 Hz,4H), 7.57 (d, J = 8.6 Hz, 2 H),7.73-7.89 (m, 6 H), 8.88 (s, 1 H),12.29(s, 1 H)

TABLE 1-6 Example Structural formula NMR 1-26

(DMSO-d6-300)1.56 (dd, J = 6.0, 12.0 Hz, 1 H),1.96 (dd, J = 6.0, 9.0 Hz,1 H),2.65 (t, J = 9.0 Hz, 1 H),7.17 (brd, J = 9.0 Hz, 1 H), 7.25-7.37(m, 2 H), 7.39-7.46 (m, 4 H),7.53-7.59 (m, 4 H), 7.76 (d,J = 9.0 Hz, 2H), 7.85 (d, J = 9.0 Hz,2 H), 7.88 (d, J = 9.0 Hz, 2 H) 1-27

(DMSO-d6-300)1.55 (dd, J = 6.0, 9.0 Hz, 1 H),1.55 (dd, J = 6.0, 9.0 Hz,1 H),1.73 (dd, J = 3.0, 6.0 Hz, 1 H),2.40 (t, J = 9.0 Hz, 1 H), 5.12(s,2 H), 6.75 (d, J = 9.0 Hz, 1 H),7.04 (t, J = 9.0 Hz, 1 H), 7.20-7.43(m, 6 H), 7.56 (d, J = 9.0 Hz,2 H), 7.77 (d, J = 9.0 Hz, 2 H),7.84 (d, J= 9.0 Hz, 2 H), 7.88 (d,J = 9.0 Hz, 2 H), 9.61 (s, 1 H) 1-28

(DMSO-d6-300)0.92 (d, J = 6.0 Hz, 6 H), 1.44 (dd,J = 6.0, 9.0 Hz, 1 H),1.89 (dd,J = 6.0, 12.0 Hz, 1 H), 2.66 (t,J = 9.0 Hz, 1 H), 3.85 (d, J =6.0 Hz,2 H), 6.83 (d, J = 9.0 Hz, 1 H),7.13 (t, J = 7.5 Hz, 1 H), 7.28(d,J = 9.0 Hz, 1 H), 7.57 (d, J = 9.0 Hz,2 H), 7.78 (d, J = 9.0 Hz, 2H),7.87 (s, 4 H), 8.97 (s, 1 H),9.55 (s, 1 H) 1-29

(METHANOL-d4-400)1.84 (dd, J = 6.0, 9.0 Hz, 1 H),2.09 (dd, J = 6.0, 9.0Hz, 1 H),2.77 (t, J = 9.0 Hz, 1 H), 7.11-7.25 (m, 5 H), 7.39 (t, J = 6.0Hz,1 H), 7.46 (t, J = 6.0 Hz, 2 H),7.67 (d, J = 6.0 Hz, 2 H), 7.78 (d,J= 6.0 Hz, 2 H), 7.95 (d, J = 6.0 Hz,2 H) 1-30

(METHANOL-d4-400)1.84 (dd, J = 8.0, 4.0 Hz, 1 H),2.07 (dd, J = 4.0, 8.0Hz, 1 H),2.76 (t, J = 8.0 Hz, 1 H), 7.03 (d,J = 8.0 Hz, 2 H), 7.07 (d, J= 8.0 Hz,2 H), 7.13-7.26 (m, 6 H), 7.41 (t,J = 8.0 Hz, 2 H), 7.84 (d, J= 8.0 Hz,2 H)

TABLE 1-7 Example Structural formula NMR 1-31

(METHANOL-d4-400)1.83 (dd, J = 4.0, 8.0 Hz, 1 H),2.08 (dd, J = 8.0, 4.0Hz, 1 H),2.77 (t, J = 8.0 Hz, 1 H), 7.11-7.28 (m, 5 H), 7.57-7.65 (m, 4H),7.78 (d, J = 8.0 Hz, 2 H), 7.95 (d,J = 8.0 Hz, 2 H) 1-32

(DMSO-d6-300)1.63 (dd, J = 6.0, 9.0 Hz, 1 H),2.04 (dd, J = 6.0, 9.0 Hz,1 H),2.75 (t, J = 9.0 Hz, 1 H), 7.10-7.27 (m, 5 H), 7.70 (d, J = 3.0Hz,1 H), 7.94 (d, J = 3.0 Hz, 1 H) 1-33

(ACETONE-d6-400)1.86 (dd, J = 8.0, 4.0 Hz, 1 H),2.13 (dd, J = 4.0, 8.0Hz, 1 H),2.85 (t, J = 8.0 Hz, 1 H), 4.48 (s,3 H), 7.14-7.30 (m, 5 H),8.06 (d,J = 8.0 Hz, 2 H), 8.27 (d, J = 8.0 Hz,2 H) 1-34

(ACETONE-d6-400)1.67 (t, J = 8.0 Hz, 3 H), 1.86 (dd,J = 4.0, 8.0 Hz, 1H), 2.13 (dd,J = 4.0, 8.0 Hz, 1 H), 2.82 (t,J = 8.0 Hz, 1 H), 4.81 (q, J= 8.0 Hz,2 H), 7.13-7.30 (m, 5 H), 8.06 (d,J = 8.0 Hz, 2 H), 8.28 (d, J= 8.0 Hz,2 H) 1-35

(METHANOL-d4-400)1.24 (t, J = 6.0 Hz, 3 H), 1.87 (dd,J = 8.0, 4.0 Hz, 1H), 2.02-2.13 (m, 3 H), 2.76 (t, J = 8.0 Hz,1 H), 4.70 (t, J = 6.0 Hz, 3H),7.12-7.26 (m, 5 H), 8.03 (d,J = 8.0 Hz, 2 H), 8.27 (d, J = 8.0 Hz,2H)

TABLE 1-8 Example Structural formula NMR 1-36

(METHANOL-d4-400)1.69 (d, J = 6.7 Hz, 6 H), 1.87 (dd,J = 9.8, 5.9 Hz, 1H), 2.10 (dd,J = 8.6, 5.5 Hz, 1 H), 2.7 (t,J = 9.2 Hz, 1 H), 5.19(Septet,J = 6.7 Hz, 1 H), 7.11-7.27 (m,5 H), 8.01-8.06 (m, 2 H),8.25-8.29 (m, 2 H) 1-37

(METHANOL-d4-400)1.91 (dd, J = 9.8, 5.5 Hz, H1),2.11 (dd, J = 8.6, 5.5Hz, 1 H),2.80 (t, J = 9.0 Hz, 1 H) 7.10-7.25 (m, 4 H), 7.43 (t, J = 8.1Hz,1 H), 7.53-7.58 (m, 1 H), 7.62-7.66 (m, 1 H), 7.72 (d, J = 9.4 Hz,1H), 8.01-8.05 (m, 1 H), 8.08-8.14 (m, 2 H), 8.57-8.60 (m, 1 H) 1-38

(DMSO-d6-300)1.49 (dd, J = 5.2, 9.8 Hz, 1 H),1.92 (dd, J = 5.2, 9.0 Hz,1 H),2.69 (dd, J = 9.0, 9.8 Hz, 1 H),2.92 (s, 3 H), 6.96 (d, J = 7.9Hz,1 H), 7.01 (d, J = 7.9 Hz, 1 H),7.11 (s, 1 H), 7.20 (t, J = 7.9 Hz,1H), 7.57 (d, J = 8.7 Hz, 2 H),7.78 (d, J = 8.6 Hz, 2 H), 7.87 (s,4 H),8.99 (s, 1 H), 9.67 (s, 1 H),12.17 (s, 1 H) 1-39

(DMSO-d6-300)1.62 (dd, J = 6.0, 9.0 Hz, 1 H),2.03 (dd, J = 6.0, 9.0 Hz,1 H),2.75 (t, J = 9.0 Hz, 1 H), 7.11-7.27 (m, 5 H), 7.70 (d, J = 3.0Hz,1 H), 7.94 (d, J = 3.0 Hz, 1 H) 1-40

(DMSO-d6-300)1.46 (dd, J = 6.0, 9.0 Hz, 1 H),1.89 (dd, J = 6.0, 9.0 Hz,1 H),2.01 (s, 3 H), 2.64 (t, J = 9.0 Hz,1 H), 6.86 (d, J = 9.0 Hz, 1H),7.14 (t, J = 7.5 Hz, 1 H), 7.38-7.46 (m, 2 H), 7.57 (d, J = 9.0 Hz,2H), 7.78 (d, J = 9.0 Hz, 2 H),7.87 (s, 4 H), 8.93 (brs, 1 H),9.86 (s, 1H), 12.13 (brs, 1 H)

TABLE 1-9 Example Structural formula NMR 1-41

(DMSO-d6-300)1.46 (dd, J = 6.0, 9.0 Hz, 1 H),1.88 (dd, J = 6.0, 9.0 Hz,1 H),2.64 (t, J = 9.0 Hz, 1 H), 3.64 (s,3 H), 6.83 (d, J = 9.0 Hz, 1H),7.13 (t, J = 7.5 Hz, 1 H), 7.27 (d,J = 9.0 Hz, 1 H), 7.35 (s, 1H),7.57 (d, J = 9.0 Hz, 2 H), 7.78 (d,J = 9.0 Hz, 2 H), 7.87(s, 4H),8.95 (brs, 1 H), 9.57 (s, 1 H),12.11 (brs, 1 H) 1-42

(DMSO-d6-300)1.12-1.26 (m, 2 H), 1.34-1.39 (m, 2 H), 1.40(s, 9 H),1.80-1.89 (m, 2 H) 2.56 (t, J = 9.0, 1 H), 2.80-2.96 (m, 2 H), 3.27-3.35(m,1 H), 3.81-3.89 (m, 2 H), 5.36-5.43 (m, 1 H), 6.36-6.43 (m, 3 H),6.92 (t, J = 7.5 Hz, 1 H),7.58 (d,J = 9.0 Hz, 2 H), 7.79 (d,J = 9.0 Hz,2 H),7.86 (d, J = 9.0 Hz, 2 H),7.89 (d, J = 9.0 Hz,2 H), 8.91 (s, 1 H),12.07 (s, 1 H) 1-43

(DMSO-d6-300)1.35 (dd, J = 6.0, 9.0 Hz, 1 H),1.83 (dd, J = 6.0, 9.0 Hz,1 H),2.53 (t, J = 9.0 Hz, 1 H), 4.20 (d,J = 3.0 Hz, 2 H), 6.12 (t, J =6.0 Hz,1 H), 6.37 (t, J = 6.0 Hz, 2 H),6.49 (s, 1 H), 6.89 (t, J = 7.5Hz,1 H), 7.17-7.25 (m, 1 H), 7.26-7.36 (m, 4 H), 7.26-7.36 (m, 4 H),7.57(d, J = 9.0 Hz, 2 H), 7.78 (d,J = 9.0 Hz, 2 H), 8.90 (brs, 1 H),12.07(brs, 1 H) 1-44

(DMSO-d6-300)1.42 (dd, J = 6.0, 9.0 Hz, 1 H),1.87 (dd, J = 6.0, 9.0 Hz,1 H),2.59 (t, J =9.0 Hz, 1 H), 6.57 (d,J = 9.0 Hz, 1 H), 6.63 (m, 2H),7.01 (t, J = 9.0 Hz, 1 H), 7.57 (d,J = 9.0 Hz, 2 H), 7.78 (d, J = 9.0Hz,2 H), 7.84-7.90 (m, 4 H) 1-45

(DMSO-d6-300)0.94-1.29 (m, 9 H), 1.49-1.70 (m,5 H), 7.54-7.61 (m, 2 H),7.72-7.90 (m, 6 H), 8.53-8.74 (m, 1 H)

TABLE 1-10 Example Structural formula NMR 1-46

(ACETONE-d6-500)1.84-1.92 (m, 1 H), 2.13-2.20 (m,1 H), 2.83-2.89 (m, 1H), 7.13-7.30 (m, 6 H), 7.80-7.92 (m, 1 H),8.03-8.08 (m, 3 H), 8.22-8.33(m,3 H) 1-47

(METHANOL-d4-400)1.48-1.56 (m, 1 H), 1.83-1.90 (m,1 H), 2.31-2.38 (m, 1H), 7.02-7.08 (m, 1 H), 7.09-7.16 (m, 3 H),7.18-7.22 (m, 2 H), 7.43-7.47(m,1 H), 7.49-7.52 (m, 1 H), 7.71-7.77 (m, 2 H), 7.71-7.77 (m, 2 H) 1-48

(ACETONE-d6-400)1.83-1.89 (m, 1 H), 1.96 (s, 3 H),2.09-2.15 (m, 1 H),2.82-2.89 (m,1 H), 7.14-7.30 (m, 6 H), 7.45-7.48 (m, 1 H), 7.71-7.73 (m,1 H),7.78-7.83 (m, 2 H), 7.88-7.94 (m,2 H) 1-49

(METHANOL-d4-400)1.33 (dd, J = 9.4, 5.1 Hz, 1 H),1.81 (dd, J = 7.6, 5.1Hz, 1 H),2.30 (t, J = 8.8 Hz, 1 H), 7.01-7.07 (m, 1 H), 7.09-7.16 (m, 2H),7.18-7.24 (m, 2 H), 7.40-7.44 (m,1 H), 7.50-7.54 (m, 1 H), 7.72-7.78(m, 2 H), 7.86-7.93 (m, 2 H) 1-50

(ACETONE-d6-400)1.90 (dd, J = 9.8, 5.9 Hz, 1 H),2.11 (dd, J = 8.6, 5.5Hz, 1 H),2.82 (t, J = 9.2 Hz, 1 H), 7.10-7.29 (m, 5 H), 7.47-7.52 (m, 1H),7.64-7.73 (m, 2 H), 7.86-7.94 (m,2 H), 8.02-8.06 (m, 1 H), 8.08-8.13(m, 1 H)

TABLE 1-11 Example Structural formula NMR 1-51

(DMSO-d6-300)0.99-1.64 (m, 17 H), 2.55-2.78 (m, 2 H),3.76-3.98 (m, 2H),7.57 (d, J = 6.0 Hz, 2 H), 7.78 (d,J = 9.0 Hz, 2 H), 7.80 (d, J = 9.0Hz,2 H), 7.87 (d, J = 9.0 Hz, 2 H),8.64 (brs, 1 H), 12.55 (brs, 1 H)1-52

(DMSO-d6-300)1.45 (dd, J = 9.5, 4.9 Hz, 1 H),1.77-1.85 (m, 1 H),2.51-2.61 (m,1 H), 6.79-6.86 (m, 2 H), 7.00-7.09 (m, 2 H), 7.45-7.63 (m,6 H),7.68-7.81 (m, 5 H), 7.86 (s, 4 H) 1-53

(MeOH-d4-400)1.83 (dd, J = 9.8, 5.5 Hz, 1 H),2.09 (dd, J = 8.6, 5.9 Hz,1 H),2.77 (t, J = 9.2 Hz, 1 H), 3.83 (s,3 H), 7.00-7.04 (m, 2 H),7.14-7.28 (m, 5 H), 7.61-7.66 (m, 2 H),7.73-7.77 (m, 2 H), 7.89-7.93(m,2 H) 1-54

(ACETONE-d6-400)1.88 (dd, J = 9.8, 5.5 Hz, 1 H),2.10 (dd, J = 8.6, 5.9Hz, 1 H),2.80 (t, J = 9.2 Hz, 1 H), 7.12-7.27 (m, 5 H), 7.38-7.48 (m, 2H),7.63-7.68 (m, 1 H), 7.69-7.83 (m,1 H), 7.91-8.03 (m, 3 H), 8.08 (s,1H) 1-55

(ACETONE-d6-400)1.83 (dd, J = 4.0, 8.0 Hz, 1 H),2.11 (dd, J = 4.0, 8.0Hz, 1 H),2.68 (s, 3 H), 2.86 (t, J = 10.0 Hz,1 H), 7.12-7.28 (m, 5 H),8.04 (d,J = 8.0 Hz, 2 H), 8.19 (d, J = 8.0 Hz,2 H)

TABLE 1-12 Example Structural formula NMR 1-56

(ACETONE-d6-400)1.85 (dd, J = 8.0, 12.0 Hz, 1 H),2.08-2.13 (m, 1 H),2.81 (t,J = 10.0 Hz, 1 H), 7.12-7.26 (m,5 H), 7.64-7.77 (m, 3 H), 8.08(d,J = 8.0 Hz, 2 H), 8.24 (d, J = 8.0 Hz,2 H), 8.30 (d, J = 8.0 Hz, 2 H)1-57

(ACETONE-d6-400)1.94 (dd, J = 4.0, 8.0 Hz, 1 H),2.17 (dd, J = 4.0, 8.0Hz, 1 H),2.91 (t, J = 10.0 Hz, 1 H), 7.15-7.31 (m, 5 H), 7.38-7.49 (m, 4H),7.61 (dd, J = 1.0, 4.0 Hz, 1 H),7.71 (dt, J = 8.0, 1.0 Hz, 2 H),7.95(brs, 1 H) 1-58

(DMSO-d6-300)1.85 (dd, J = 6.0, 9.0 Hz, 1 H),1.96 (dd, J = 6.0, 9.0 Hz,1 H),2.77 (t, J = 9.0 Hz, 1 H), 6.61-6.71 (m, 2 H), 6.81 (d, J = 6.0Hz,1 H), 7.01-7.09 (m, 1 H), 7.58 (d,J = 9.0 Hz, 2 H), 7.71-7.90 (m,7H), 9.45 (brs, 1 H), 12.39 (brs,1 H) 1-59

(ACETONE-d6-400)1.86 (dd, J = 4.0, 8.0 Hz, 1 H),2.05-2.09 (m, 1 H), 2.78(t,J = 10.0 Hz, 1 H), 7.13-7.26 (m,5 H), 7.62-7.68 (m, 3 H), 8.10 (d,J =8.0 Hz, 2 H), 8.20 (dd, J = 4.0,8.0 Hz, 2 H), 8.32 (d, J = 8.0 Hz,2 H)1-60

(CDCL3-400)2.13-2.22 (m, 2 H), 2.98 (t,J = 10.0 Hz, 1 H), 5.93 (s, 1H),6.94 (d, J = 4.0 Hz, 1 H), 7.17-7.22 (m, 2 H), 7.24-7.33 (m, 3H),7.36 (d, J = 4.0 Hz, 1 H)

TABLE 1-13 Example Structural formula NMR 1-61

(DMSO-d6-300)1.45 (dd, J = 5.2, 9.4 Hz, 1 H),1.92 (dd, J = 5.2, 8.7 Hz,1 H),2.67 (dd, J = 8.7, 9.4 Hz, 1 H),6.68-6.76(m, 2 H), 6.82 (d,J = 8.3Hz, 1 H), 7.12 (t, J = 7.9 Hz,1 H), 7.42 (s, 1 H), 7.49-7.61 (m,2 H),7.57 (d, J = 8.7 Hz, 2 H),7.78 (d, J = 8.7 Hz, 2 H), 7.88 (s,4 H),8.13(dd, J = 1.1, 4.9 Hz,1 H), 8.93 (s, 1 H), 8.96 (s, 1 H),12.13 (s, 1 H)1-62

(DMSO-d6-300)1.47-1.57(m, 1 H), 1.83-1.95 (m,1 H), 2.54-2.65 (m, 1 H),6.96 (d,J = 9.0 Hz, 1 H), 7.19 (t, J = 7.5 Hz,1 H), 7.55 (d, J = 9.0 Hz,2 H),7.64-7.73 (m, 3 H), 7.77 (d,J = 9.0 Hz, 2 H), 7.83-7.93 (m,4 H),8.07 (t, J = 7.5 Hz, 1 H),8.15 (d, J = 9.0 Hz, 1 H), 8.708.74 (m, 1 H),10.45 (brs, 1 H) 1-63

(DMSO-d6-300)1.51 (dd, J = 6.0, 9.0 Hz, 1 H),1.95 (dd, J = 6.0, 9.0 Hz,1 H),2.73 (t, J = 9.0 Hz, 1 H), 6.99 (d,J = 9.0 Hz, 1 H), 7.25 (t, J =7.5 Hz,4 H), 7.57 (d, J = 9.0 Hz, 2 H),7.59 (t, J = 9.0 Hz, 1 H), 7.70(s,1 H), 7.78 (d, J = 9.0 Hz, 2 H),7.84 (d, J = 6.0 Hz,2 H), 7.86-7.91(m, 4 H), 8.78 (d, J = 6.0 Hz,2 H), 8.99 (s, 1 H), 10.46 (s,1 H), 12.16(brs, 1 H) 1-64

(DMSO-d6-400)1.51 (dd, J = 9.5, 4.6 Hz, 1 H),1.89-1.95 (m, 1 H),2.60-2.72 (m,1 H), 6.95 (d, J = 8.3 Hz, 1 H),7.21 (t, J = 8.3 Hz, 1 H),7.49-7.78 (m, 8 H), 7.87 (s, 4 H),8.24-8.28 (m, 1 H), 8.74 (dd,J = 4.9,1.6 Hz, 1 H), 9.07 (d,J = 1.9 Hz, 1 H), 10.39 (s, 1 H) 1-65

(DMSO-d6-300)1.42 (dd, J = 5.4, 9.3 Hz, 1 H),1.92 (t, J = 7.4 Hz, 1 H),2.63 (t,J = 9.4 Hz, 1 H), 5.22 (s, 2 H),7.10-7.29 (m, 7 H), 7.49 (dd,J =2.1, 8.1 Hz, 1 H), 7.64 (d,J = 8.1 Hz, 1 H), 7.71 (d, J = 2.1 Hz,1 H),7.74 (d, J = 9.0 Hz, 2 H),8.71 (brs, 1 H),12.07 (brs, 1 H)

TABLE 1-14 Example Structural formula NMR 1-66

(DMSO-d6-300)1.41-1.50 (m, 1 H), 1.88-1.97 (m,1 H), 2.64 (t, J = 9.0 Hz,1 H),3.64 (br, 2 H), 3.86 (br, 2 H),4.78 (br, 1 H), 6.71-6.80 (m,3 H),7.14 (t, J = 7.5 Hz, 1 H),7.57 (d, J = 6.0 Hz, 2 H), 7.78 (d,J = 6.0 Hz,2 H), 7.83 (br,4 H),8.81 (br, 1 H) 1-67

(DMSO-d6-300)1.39-1.55 (m, 1 H), 1.86-1.96 (m,1 H), 2.26 (s, 6 H),2.58-2.68 (m,1 H), 3.03 (s, 2 H), 6.85-6.90 (m,1 H), 7.15 (t, J = 7.5Hz, 1 H),7.45-7.72 (m, 5 H), 7.75-7.81 (m,2 H), 7.87 (s, 4 H), 9.60 (s,1 H) 1-68

(DMSO-d6-300)1.51-1.59 (m, 1 H), 1.70-1.79 (m,1 H), 2.39-2.52 (m, 1 H),6.75-6.88 (m, 2 H), 6.99 (d, J = 9.0 Hz,1 H), 7.20 (t, J = 9.0 Hz, 1H),7.31-7.40 (m, 2 H), 7.55 (d,J = 6.0 Hz, 2 H), 7.75 (d, J = 6.0 Hz,2H), 7.83 (d, J = 9.0 Hz, 2 H),7.89 (d, J = 9.0 Hz, 2 H), 8.28-8.32 (m, 2H) 1-69

(ACETONE-d6-400)1.96 (dd, J = 4.0, 8.0 Hz, 1 H),2.19 (dd, J = 4.0, 8.0Hz, 1 H),2.92 (t, J = 8.0 Hz, 1 H), 7.15-7.33 (m, 5 H), 7.47-7.54 (m, 3H),7.62 (d, J = 4.0 Hz, 1 H), 7.74 (d,J = 8.0 Hz, 2 H), 8.00 (s, 1 H)1-70

(ACETONE-d6-400)1.95 (dd, J = 8.0, 12.0 Hz, 1 H),2.17 (dd, J = 8.0, 12.0Hz, 1 H),2.91 (t, J = 10.0 Hz, 1 H), 3.85 (s,3 H), 7.02 (d, J = 8.0 Hz,2 H),7.15-7.34 (m, 6 H), 7.57 (d,J = 4.0 Hz, 1 H), 7.64 (d, J = 8.0 Hz,2H), 7.86 (s, 1 H)

TABLE 1-15 Example Structural formula NMR 1-71

(ACETONE-d6-400)1.95 (dd, J = 8.0, 8.0 Hz, 1 H),2.18 (dd, J = 8.0, 8.0Hz, 1 H),2.93 (t, J = 10.0 Hz, 1 H), 3.17 (s,6 H), 7.15-7.33 (m, 5 H),7.53 (d,J = 4.0 Hz, 1 H), 7.63 (d, J = 8.0 Hz,1 H), 7.87 (d, J = 12.0Hz, 2 H),7.92 (d, J = 8.0 Hz, 2 H) 1-72

(DMSO-d6-300)1.50 (dd, J = 6.0,9.0 Hz, 1 H),1.96 (dd, J = 6.0,9.0 Hz, 1H),2.68 (t, J = 9.0 Hz, 1 H), 4.05 (s,2 H), 7.11-7.29 (m, 5 H),7.64 (dd,J = 3.0, 9.0 Hz, 1 H),7.83 (dd, J = 3.0, 9.0 Hz, 1 H),7.87 (d, J = 3.0Hz, 1 H), 7.98 (d,J = 9.0 Hz, 1 H), 8.00 (d,J = 3.0 Hz,1 H), 8.10 (d, J= 6.0 Hz, 1 H),8.88 (brs, 1 H), 12.04 (brs, 1 H) 1-73

(DMSO-d6-300)1.47 (dd, J = 6.0, 9.0 Hz, 1 H),1.72 (br, 4 H), 1.95 (dd, J= 6.0,9.0 Hz, 1 H), 2.65 (t, J = 9.0 Hz,1 H), 2.76 (br, 4 H), 3.01 (br,2H), 4.08 (t, J = 4.5 Hz, 2 H),6.74-6.85 (m, 3 H), 7.16 (t,J = 7.5 Hz, 1H), 7.57 (d, J = 9.0 Hz,2 H), 7.78 (d, J = 9.0 Hz, 2 H),7.85 (br, 4 H),8.83 (br, 1 H) 1-74

(DMSO-d6-300)1.58-1.71 (m, 2 H), 2.26 (t,J = 9.0 Hz, 1 H), 2.41 (t, J =6.0 Hz,4 H), 2.57 (t, J = 6.0 Hz, 2 H),3.55 (t, J = 4.5 Hz, 4 H), 3.91(t,J = 6.0 Hz, 2 H), 6.97 (t, J = 9.0 Hz,1 H), 7.57 (d, J = 9.0 Hz, 2H),7.75-7.93 (m, 7 H) 1-75

(DMSO-d6-300)1.54 (dd, J = 6.0, 9.0 Hz, 1 H),1.77-1.87 (m, 1 H), 4.23(t,J = 4.5 Hz, 2 H), 4.44 (t, J = 4.5 Hz,2 H), 6.22 (t, J = 3.0 Hz, 1H),6.63-6.76 (m, 3 H), 7.07 (t,J = 7.5 Hz, 1 H), 7.44 (dd, J = 0.0,0.0Hz, 1 H), 7.56 (d, J = 9.0 Hz,2 H), 7.74 (d, J = 3.0 Hz, 1 H),7.77 (d, J= 9.0 Hz, 2 H), 7.81-7.89 (m, 4 H)

TABLE 1-16 Example Structural formula NMR 1-76

(DMSO-d6-300)1.47 (dd, J = 6.0, 9.0 Hz, 1 H),1.97 (dd, J = 6.0, 9.0 Hz,1 H),2.68 (t, J = 9.0 Hz, 1 H), 5.15 (s,2 H), 6.82-6.91 (m, 3 H), 7.19(t,J = 9.0 Hz, 1 H), 7.57 (d, J = 9.0 Hz,2 H), 7.66 (dd, J = 6.0, 9.0Hz,1 H), 7.78 (d, J = 9.0 Hz, 2 H),7.85-7.92 (m, 4 H),8.12 (d,J = 9.0Hz, 1 H), 8.67 (d,J = 6.0 Hz,1 H), 8.78 (s, 1 H), 8.94 (s, 1H),11.91-12.38 (m, 1 H) 1-77

(DMSO-d6-400)1.44 (dd, J = 9.8, 5.2 Hz, 1 H),1.87(dd, J = 8.2, 5.5 Hz,1H),2.28(s, 3H), 2.48-2.58(m, 3H),2.69-2.73 (m, 2 H), 3.36 (s, 2H),6.75-6.79 (m, 1 H), 6.91 (s, 2 H),7.53-7.58(m, 2 H), 7.71-7.80 (m,3H), 7.85 (s, 4 H) 1-78

(DMSO-d6-400)0.99 (d, J = 6.5 Hz, 6 H), 1.45 (dd,J = 10.0, 5.1 Hz, 1 H),1.78-1.84 (m, 1 H), 2.45-2.49 (m, 1 H),2.57-2.69 (m, 4 H), 2.72-2.83(m,1 H), 3.46 (s, 2 H), 6.64-6.72 (m,1 H), 6.86 (s, 2 H), 7.52-7.58 (m,2H), 7.71-7.79 (m, 3 H), 7.85 (s,4 H) 1-79

(DMSO-d6-400)1.47 (dd, J = 9.8, 4.7 Hz, 1 H),1.72-1.78 (m, 1 H),2.37-2.44 (m,1 H), 2.56-2.62 (m, 2 H), 2.67-2.72 (m, 2 H), 3.36 (s, 2H),3.56 (s, 2 H), 6.60-6.64 (m, 1 H),6.85 (s, 2 H), 7.21-7.27 (m, 1H),7.29-7.33 (m, 4 H), 7.53-7.58 (m,2 H), 7.73-7.77 (m, 2 H), 7.80-7.87(m, 5 H) 1-80

(ACETONE-d4-400)1.87 (dd, J = 5.9, 9.8 Hz, 1 H),2.11 (dd, J = 5.9, 8.7Hz, 1 H),2.82 (dd, J = 8.7, 9.8 Hz, 1 H),4.05 (s, 2 H), 7.11-7.28 (m, 6H),7.41-7.47 (m, 1 H), 7.65-7.74 (brs, 1 H), 7.90-7.94 (m,1 H),7.98-8.03 (m, 2 H), 8.06-8.09 (m, 1 H)

TABLE 1-17 Example Structural formula NMR 1-81

(ACETONE-d4-400)2.01-2.06 (m, 1 H), 2.21 (dd,J = 5.9, 7.9 Hz, 1 H), 2.72(dd,J = 7.9, 9.4 Hz, 1 H), 4.06 (s,2 H), 6.85 (s, 1 H), 7.14-7.20 (m,2H), 7.20-7.30 (m, 4 H), 7.46 (d,J = 9.0 Hz, 1 H), 7.85 (d, J = 8.2 Hz,1H), 7.96 (s, 1 H), 8.00 (d,J = 8.2 Hz, 1 H), 8.03 (dd, J = 8.6,5.5 Hz, 1H) 1-82

(METHANOL-d4-400)1.42 (t, J = 7.5 Hz, 3 H), 1.76-1.88 (m, 1 H),2.00-2.14 (m, 1 H),2.66-2.77 (m, 1 H), 3.09 (q,J = 7.5 Hz, 2 H),7.10-7.30 (m,5 H), 7.85 (s, 1 H), 7.93 (d,J = 7.9 Hz, 2 H), 8.07 (d, J =7.9 Hz,2 H) 1-83

(DMSO-d6-300)1.46 (dd, J = 6.0, 12.0 Hz, 1 H),1.95 (dd, J = 6.0, 9.0 Hz,1 H),2.66 (t, J = 7.5 Hz, 1 H), 4.21 (t,J = 6.0 Hz, 2 H), 4.41 (t, J =6.0 Hz,2 H), 6.72-6.84 (m, 3 H), 7.10-7.19 (m, 2 H), 7.39 (s, 1 H),7.57(d, J = 9.0 Hz, 2 H), 7.78 (d,J = 9.0 Hz, 2 H), 7.82-7.91 (m,4 H),8.13(s, 1 H), 8.91 (s, 1 H) 1-84

(DMSO-d6-300)1.62-1.76 (m, 1 H), 1.93-2.05 (m,1 H), 2.62-2.74 (m, 1 H),5.16 (s,2 H), 6.79 (t, J = 7.5 Hz, 1 H),6.86 (d, J = 9.0 Hz, 1 H),7.02-7.14 (m, 2 H), 7.24-7.39 (m, 3 H),7.47-7.61 (m, 6 H), 7.76 (d,J =9.0 Hz, 2 H), 8.91 (brs, 1 H),12.17 (brs, 1 H) 1-85

(ACETONE-d6-300)1.94 (dd, J = 6.0, 9.0 Hz, 1 H),2.16 (dd, J = 6.0, 9.0Hz, 1 H),2.91 (t, J = 10.5 Hz, 1 H), 7.15-7.31 (m, 5 H), 7.44-7.52 (m, 3H),7.61 (d, J = 3.0 Hz, 1 H), 7.74 (d,J = 9.0 Hz, 2 H), 7.95 (brs, 1 H)

TABLE 1-18 Example Structural formula NMR 1-86

(DMSO-d6-300)1.71 (dd, J = 6.0, 9.0 Hz, 1 H),1.78 (dd, J = 6.0, 9.0 Hz,1 H),2.27 (t, J = 9.0 Hz, 1 H), 3.64 (t,J = 6.0 Hz, 2 H), 3.86 (t, J =6.0 Hz,2 H), 6.61 (dd, J = 3.0., 9.0 Hz,1 H), 6.69-6.73 (m, 2 H), 7.00(t,J = 9.0 Hz, 1 H), 7.52 (d, J = 9.0 Hz,2 H), 7.55 (d, J = 6.0 Hz, 1H),7.59(d, J = 6.0 Hz, 1 H) 1-87

(DMSO-d6-300)0.82 (dd, J = 3.0, 9.0 Hz, 1 H),0.99 (dd, J = 6.0, 9.0 Hz,1 H),2.70 (t, J = 10.5 Hz, 1 H), 5.17 (s,2 H), 6.76-6.89 (m, 2 H),7.02-7.14 (m, 2 H), 7.26-7.41 (m, 3 H),7.43-7.58 (m, 6 H), 7.60-7.67(m,2 H), 8.98 (br, 1 H), 11.96 (br,1 H) 1-88

(DMSO-d6-300)1.63 (dd, J = 6.0, 9.0 Hz, 1 H),2.02 (dd, J = 6.0, 9.0 Hz,1 H),2.77 (t, J = 9.0 Hz, 1 H), 6.88-6.96 (m, 2 H), 7.08 (d, J = 6.0Hz,1 H), 7.28-7.44 (m, 3 H), 7.49-7.59 (m, 4 H), 7.75 (d, J = 9.0 Hz,2H), 8.31-8.37 (m, 2 H), 9.16 (s,1 H), 12.33 (brs, 1 H) 1-89

(DMSO-d6-300)1.71 (dd, J = 6.0, 9.0 Hz, 1 H),1.99 (dd, J = 6.0, 9.0 Hz,1 H),2.70 (t, J = 9.0 Hz, 1 H), 7.11-7.27 (m, 5 H), 7.40 (t, J = 7.5Hz,1 H), 7.54 (t, J = 7.5 Hz, 2 H),7.90 (d, J = 6.0 Hz, 2 H), 7.99 (s,1H), 8.97 (s, 1 H), 12.01 (br,1 H) 1-90

(DMSO-d6-300)1.38 (dd, J = 9.5, 5.5 Hz, 1 H),1.87 (dd, J = 8.8, 5.5 Hz,1 H),2.56 (t, J = 9.0 Hz, 1 H), 4.07 (s,2 H), 5.62-5.73 (m, 1 H),6.37-6.55 (m, 3 H), 6.87-6.98. (m, 2 H),7.53-7.61 (m, 3 H), 7.74-7.81(m,2 H), 7.87 (s, 4 H)

TABLE 1-19 Example Structural formula NMR 1-91

(DMSO-d6-300)1.50 (dd, J = 6.0, 9.0 Hz, 1 H),1.96 (dd, J = 6.0, 9.0 Hz,1 H),2.68 (t, J = 9.0 Hz, 1 H), 4.05 (s,2 H), 7.13-7.28 (m, 5 H),7.64(dd, J = 3.0, 9.0 Hz, 1 H),7.83 (dd, J = 3.0, 9.0 Hz, 1 H),7.87 (d, J =0.0 Hz, 1 H), 7.98 (d,J = 9.0 Hz, 1 H), 8.00 (d, J = 0.0 Hz,1 H), 8.10(d, J = 9.0 Hz, 1 H),8.83 (brs, 1 H), 11.98 (brs, 1 H) 1-92

(METHANOL-d4-400)1.81 (dd, J = 5.5, 9.8 Hz, 1 H),2.03-2.09 (m, 1 H),2.72 (dd,J = 9.0, 9.8 Hz, 1 H), 2.75 (s,3 H), 7.10-7.28 (m, 5 H), 7.83(s,1 H), 7.92 (d, J = 8.6 Hz, 2 H),8.05 (d, J = 8.7 Hz, 2 H) 1-93

(METHANOL-d4-400)1.44 (d, J = 6.7 Hz, 3 H), 1.72 (dd,J = 5.1, 9.4 Hz, 1H), 1.99-2.06 (m, 1 H), 2.67 (dd, J = 9.0,9.4 Hz, 1 H), 4.82-4.94 (m, 1H),7.10-7.25 (m, 5 H), 7.53 (d,J = 8.3 Hz, 2 H), 7.85 (d, J = 8.2 Hz,2H) 1-94

(ACETONE-d4-400)1.88 (dd, J = 5.9, 9.8 Hz, 1 H),2.12 (dd, J = 5.9, 8.6Hz, 1 H),2.84 (dd, J = 8.6, 9.8 Hz, 1 H),4.04 (s, 2 H), 7.12-7.29 (m, 5H),7.47 (d, J = 8.2 Hz, 1 H), 7.67 (s,1 H), 7.94 (d, J = 8.2 Hz, 1H),7.97 (d, J = 8.2 Hz, 1 H), 8.02 (d,J = 8.2 Hz, 1 H), 8.09 (s, 1 H)1-95

(ACETONE-d6-400)0.93 (dd, J = 4.0, 8.0 Hz, 1 H),1.07 (dd, J = 4.0, 8.0Hz, 1 H),2.90 (t, J = 8.0 Hz, 1 H), 7.13-7.30 (m, 5 H), 7.78 (t, J = 8.0Hz,1 H), 7.88 (br, 1 H), 7.94 (d,J = 12.0 Hz, 1 H), 8.06-8.11 (m,1 H),8.32 (d, J = 12.0 Hz, 1 H),8.39-8.41 (m, 1 H), 8.67-8.68 (m,1 H)

TABLE 1-20 Example Structural formula NMR 1-96

(ACETONE-d6-400)2.08-2.09 (m, 1 H), 1.11 (dd,J = 4.0, 8.0 Hz, 1 H), 2.74(t,J = 8.0 Hz, 1 H), 4.12 (s, 2 H),6.93 (br, 1 H), 7.16-7.18 (m,2 H),7.24-7.29 (m, 3 H), 7.42-7.50 (m, 2 H), 7.66 (brd,J = 8.0 Hz, 1 H), 7.91(brd,J = 8.0 Hz, 1 H), 8.00 (br, 1 H),8.53 (d, J = 8.0 Hz, 1 H) 1-97

(DMSO-d6-300)1.69 (dd, J = 6.0, 9.0 Hz, 1 H),2.01 (dd, J = 6.0, 9.0 Hz,1 H),2.74 (t, J = 9.0 Hz, 1 H), 7.16-7.28 (m, 5 H), 7.60 (d, J = 9.0Hz,2 H), 7.95 (d, J = 9.0 Hz, 2 H),8.01 (s, 1 H), 9.02 (s, 1 H),12.13(br, 1 H) 1-98

(DMSO-d6-300)1.65 (dd, J = 6.0, 9.0 Hz, 1 H),1.99 (dd, J = 6.0, 9.0 Hz,1 H),2.09 (s, 6 H), 2.69 (t, J = 9.0 Hz,1 H), 3.30 (s, 2 H), 7.04-7.21(m,4 H), 7.50-7.59 (m, 4 H), 7.76 (d,J = 9.0 Hz, 2 H) 1-99

(DMSO-d6-300)1.30-1.48 (m, 3 H), 1.81-1.93 (m,3 H), 2.28 (s, 3 H),2.17-2.32 (m,1 H), 2.46-2.59 (m, 1 H), 2.78-2.92 (m, 2 H), 3.08-3.25 (m,2 H),5.34 (brs, 1 H), 6.32-6.45 (m,3 H), 6.90 (t, J = 9.0 Hz, 1 H),7.57(d, J = 9.0 Hz, 2 H), 7.78 (d,J = 9.0 Hz, 2 H), 7.82-7.91 (m,4 H), 8.83(brs, 1 H) 1-100

(DMSO-d6-300)1.70 (dd, J = 5.6, 9.8 Hz, 1 H),2.07 (dd, J = 5.6, 8.7 Hz,1 H),2.81 (dd, J = 8.7, 9.8 Hz, 1 H),7.14-7.30 (m, 5 H), 7.62 (d,J = 8.7Hz, 2 H), 8.03 (d, J = 9.1 Hz,2 H), 8.27 (s, 1 H), 9.49 (s, 1 H),12.27(s, 1 H)

TABLE 1-21 Example Structural formula NMR 1-101

(DMSO-d6-300)1.42 (dd, J = 10.3, 5.5 Hz, 1 H),1.83 (dd, J = 8.4, 5.2 Hz,1 H),2.45-2.54 (m, 1 H), 3.60 (s, 3 H),4.20 (d, J = 4.4 Hz, 2 H),5.82-5.90 (m, 1 H), 6.42 (d, J = 7.7 Hz,1 H), 6.51-6.59 (m, 2 H), 6.78(s,1 H), 6.91 (t, J = 7.3 Hz, 1 H),7.05 (s, 1 H), 7.57 (d, J = 8.4 Hz,2H), 7.78 (d, J = 8.4 Hz, 2 H),7.87 (s, 4 H) 1-102

(DMSO-d6-300)0.81 (dd, J = 6.0, 9.0 Hz, 1 H),0.98 (dd, J = 6.0, 9.0 Hz,1 H),2.60 (t, J = 9.0 Hz, 1 H), 6.62-6.76 (m, 2 H), 6.93-7.05 (m, 2H),7.49-7.61 (m, 4 H), 7.72-7.80 (m,2 H), 8.99 (br, 1 H), 9.16 (br,1 H),11.92 (br, 1 H) 1-103

(DMSO-d6-300)1.65 (dd, J = 6.0, 9.0 Hz, 1 H),1.97 (dd, J = 6.0, 9.0 Hz,1 H),2.13 (s, 3 H), 2.23-2.36 (m, 8 H),2.66 (t, J = 9.0 Hz, 1 H),7.04-7.21 (m, 4 H), 7.49-7.59 (m, 4 H),7.76 (d, J = 9.0 Hz, 2 H) 1-104

(DMSO-d6-300)1.01-1.50 (m, 4 H), 1.62 (dd,J = 6.0, 9.0 Hz, 1 H),1.85-1.92 (m, 1 H), 2.14 (s, 3 H),2.23-2.31 (m, 2 H), 2.37 (s, 3H),2.81-2.96 (m, 3 H), 7.05-7.19 (m,4 H), 7.48-7.57 (m, 4 H), 7.73 (d,J= 9.0 Hz, 2 H) 1-105

(METHANOL-d4-300)1.85 (dd, J = 6.0, 9.0 Hz, 1 H),2.06 (dd, J = 6.0, 9.0Hz, 1 H),2.73 (t, J = 9.0 Hz, 1 H), 4.07 (s,2 H), 7.03 (d, J = 9.0 Hz, 1H),7.17 (t, J = 9.0 Hz, 1 H), 7.42-7.50 (m, 4 H), 7.67 (d, J = 9.0 Hz,2H), 7.78 (d, J = 9.0 Hz, 2 H),7.96 (d, J = 9.0 Hz, 2 H)

TABLE 1-22 Example Structural formula NMR 1-106

(DMSO-d6-300)1.62 (dd, J = 6.0, 12.0 Hz, 1 H),1.98 (dd, J = 6.0, 9.0 Hz,1 H),2.26 (s, 3 H), 2.67 (t, J = 9.0 Hz,1 H), 7.15-7.27 (m, 5 H), 7.47(s,1 H), 7.54 (d, J = 9.0 Hz, 2 H),7.55 (d, J = 9.0 Hz, 2 H) 1-107

(DMSO-d6-300)1.60 (dd, J = 6.0, 9.0 Hz, 1 H),2.01 (dd, J = 6.0, 9.0 Hz,1 H),2.74 (t, J = 9.0 Hz, 1 H), 5.18 (s,2 H), 6.85-6.92 (m, 3 H), 7.21(t,J = 7.5 Hz, 1 H), 7.53 (d, J = 9.0 Hz,2 H), 7.56 (d, J = 6.0 Hz, 1H),7.58 (d, J = 6.0 Hz, 1 H), 7.68-7.75 (m, 1 H), 7.76(d, J = 9.0 Hz,2H), 8.17-8.21 (m, 1 H), 8.70 (d,J = 6.0 Hz, 1 H), 8.81 (s, 1 H),9.18 (s,1 H), 12.20 (brs, 1 H) 1-108

(DMSO-d6-300)1.59 (dd, J = 6.0, 12.0 Hz, 1 H),2.00 (dd, J = 6.0, 9.0 Hz,1 H),2.73 (t, J = 9.0 Hz, 1 H), 5.11 (s,2 H), 6.82-6.88 (m, 2 H), 6.89(s,1 H), 7.18 (t, J = 7.5 Hz, 1 H),7.34 (dd, J = 6.0, 9.0 Hz, 1 H),7.49(d, J = 6.0 Hz, 2 H), 7.53 (t,J = 3.0 Hz, 1 H), 7.56 (d, J = 3.0 Hz,1H), 7.58 (d, J = 3.0 Hz, 1 H),7.76 (d, J = 9.0 Hz, 2 H), 7.82 (dt,J =3.0, 9.0 Hz, 1 H), 7.55-7.59 (m, 1 H), 9.17 (s, 1 H),12.23 (brs, 1 H)1-109

(DMSO-d6-300)1.50 (dd, J = 5.7, 9.8 Hz, 1 H),1.96 (dd, J = 5.7, 8.3 Hz,1 H),2.68 (dd, J = 8.3, 9.8 Hz, 1 H),4.05 (s, 2 H), 7.12-7.28 (m, 5H),7.64 (dd, J = 1.5, 8.3 Hz, 1 H),7.83 (dd, J = 1.5, 8.3 Hz, 1 H),7.87(d, J = 1.5 Hz, 1 H), 7.98 (d,J = 8.3 Hz, 1 H), 8.00 (d,J = 1.5 Hz,1 H),8.10 (d, J = 8.3 Hz, 1 H),8.88 (s, 1 H), 12.05 (s, 1 H) 1-110

(DMSO-d6-300)1.62 (dd, J = 5.7, 9.8 Hz, 1 H),2.04 (dd, J = 5.7, 8.7 Hz,1 H),2.76 (dd, J = 8.7, 9.8 Hz, 1 H),7.15-7.30 (m, 5 H), 7.43-7.53 (m,2H), 7.57 (d, J = 3.8 Hz, 1 H),7.65 (d, J = 3.7 Hz, 1 H),7.68 (ddd, J =1.8, 2.7, 6.4 Hz,1 H), 7.81-7.84 (m, 1 H), 9.21 (s,1 H), 12.20 (s, 1 H)

TABLE 1-23 Example Structural formula NMR 1-111

(DMSO-d6-300)1.49 (dd, J = 9.5, 5.5 Hz, 1 H),1.73 (dd, J = 8.2, 4.9 Hz,1 H),2.39 (t, J = 9.2 Hz, 1 H), 6.69-6.79 (m, 3 H), 6.91-6.99 (m, 2 H),7.50 (dd, J = 8.1, 4.8 Hz,1 H), 7.56 (d, J = 8.4 Hz, 2 H),7.78 (d, J =8.4 Hz, 2 H), 7.81-7.91 (m, 4 H), 8.00-8.08 (m, 1 H),8.65-8.70 (m, 1 H),8.85(d, J = 2.2 Hz, 1 H) 1-112

(DMSO-d6-300)1.37 (dd, J = 9.9, 5.5 Hz, 1 H),1.86 (dd, J = 8.1, 5.6 Hz,1 H),2.56 (t, J = 9.5 Hz, 1 H),4.18 (d, J = 4.4 Hz, 2 H), 5.86-5.93 (m,1 H), 6.40-6.55 (m, 2 H), 6.89-6.96 (m, 3 H),7.53-7.61 (m, 2 H),7.74-7.82 (m, 2 H), 7.87 (s, 4 H) 1-113

(DMSO-d6-300)1.69 (dd, J = 6.0, 9.0 Hz, 1 H),2.06 (dd, J = 6.0, 9.0 Hz,1 H),2.81 (t, J = 9.0 Hz, 1 H), 7.34-7.47 (m, 2 H), 7.49-7.59 (m, 4H),7.72-7.80 (m, 3 H), 7.86 (s, 1 H) 1-114

(DMSO-d6-300)1.46 (dd, J = 3.0, 9.0 Hz, 1 H),1.93 (dd, J = 6.0, 9.0 Hz,1 H),2.63 (t, J = 9.0 Hz, 1 H), 2.83 (s,3 H), 2.98 (s, 3 H), 4.70 (s, 2H),6.68-6.83 (m, 3 H), 7.13 (t,J = 9.0 Hz, 1 H), 7.57 (d, J = 9.0 Hz,2H), 7.78 (d, J = 9.0 Hz, 2 H),7.83-7.91 (m, 4 H), 8.89 (brs,1 H), 12.16(brs, 1 H) 1-115

(DMSO-d6-300)1.66-1.74 (m, 1 H), 1.78-1.87 (m,1 H), 2.34-2.45 (m, 1 H),3.66 (s,3 H), 6.63-6.77 (m, 3 H), 7.03-7.10 (m, 1 H), 7.52 (d, J = 9.0Hz,2 H), 7.54-7.59 (m, 2 H), 7.75 (d,J = 9.0 Hz, 2 H)

TABLE 1-24 Example Structural formula NMR 1-116

(DMSO-d6-300)1.55-1.61 (m, 1 H) 1.85-1.93 (m,1 H), 2.58 (t, J = 9.0 Hz,1 H),6.53-6.65 (m, 3 H), 7.00 (t,J = 7.5 Hz, 1 H), 7.51-7.58 (m,4 H),7.75 (d, J = 6.0 Hz, 1 H) 1-117

(DMSO-d6-300)1.47 (dd, J = 6.0, 9.0 Hz, 1 H),1.95 (dd, J = 6.0, 9.0 Hz,1 H),2.66 (t, J = 9.0 Hz, 1 H), 4.34 (s,2 H), 6.73-6.86 (m, 3 H), 7.17(t,J = 7.5 Hz, 1 H), 7.36 (brs, 1 H),7.47 (brs, 1 H), 7.57 (d,J = 9.0Hz, 2 H), 7.78 (d, J = 9.0 Hz,2 H), 7.82-7.91 (m, 4 H),8.93 (brs, 1 H),12.14 (brs, 1 H) 1-118

(DMSO-d6-300)1.47 (dd, J = 6.0, 9.0 Hz, 1 H),1.95 (dd, J = 6.0, 9.0 Hz,1 H),2.65 (d, J = 6.0 Hz, 3 H), 2.69 (t,J = 4.5 Hz, 1 H), 4.38 (s, 2H),6.74-6.86 (m, 3 H), 7.17 (t,J = 9.0 Hz, 1 H), 7.57 (d, J = 9.0 Hz,2H), 7.78 (d, J = 9.0 Hz, 2 H),7.83-7.91 (m, 4 H), 7.98 (brs,)1 H), 8.92(s, 1 H), 12.13 (brs,1 H) 1-119

(DMSO-d6-300)1.45 (dd, J = 6.0, 9.0 Hz, 1 H),1.95 (dd, J = 6.0, 9.0 Hz,1 H),2.65 (t, J = 9.0 Hz, 1 H), 4.59 (s,2 H), 6.68-6.84 (m, 3 H), 7.16(t,J = 7.5 Hz, 1 H), 7.57 (d, J = 9.0 Hz,2 H), 7.78 (d, J = 9.0 Hz, 2H),7.83-7.91 (m, 4 H), 8.92 (s, 1 H),12.18 (brs, 1 H), 12.91 (brs, 1 H)1-120

(ACETONE-d6-400)1.94-1.99 (m, 1 H), 2.17-2.22 (m,1 H), 2.94 (t, J = 10.0Hz, 1 H),6.94 (d, J = 1.0 Hz, 1 H), 7.16-7.31 (m, 5 H), 7.65 (d, J = 4.0Hz,1 H), 7.69 (d, J = 4.0 Hz, 1 H),8.55 (d, J = 1.0 Hz, 1 H)

TABLE 1-25 Example Structural formula NMR 1-121

(ACETONE-d6-400)0.97 (dd, J = 8.0, 12.0 Hz, 1 H),1.10 (dd, J = 8.0, 12.0Hz, 1 H),2.95 (t, J = 8.0 Hz, 1 H), 7.17-7.31 (m, 5 H), 7.72 (d, J = 8.0Hz,1 H), 7.81 (d, J = 8.0 Hz, 1 H),7.82-7.85(m, 2 H), 8.24 (br, 1 H)1-122

(ACETONE-d6-400)0.95 (dd, J = 8.0, 12.0 Hz, 1 H),1.07 (dd, J = 8.0, 8.0Hz, 1 H),2.87 (t, J = 8.0 Hz, 1 H), 7.13-7.27 (m, 5 H), 7.13-7.27(m, 5H),3.74 (dt, J = 12.0, 2.0 Hz, 1 H),7.82 (d, J = 4.0 Hz, 1 H), 3.97(dt,J = 8.0, 2.0 Hz, 1 H), 3.97 (dt,J = 8.0, 2.0 Hz, 1 H), 8.21 (d,J =8.0 Hz, 1 H), 8.28 (d, J = 8.0 Hz,1 H) 1-123

(ACETONE-d6-400)1.28-1.32 (m, 1 H), 0.95 (dd,J = 8.0, 12.0 Hz, 1 H),2.13-2.17 (m, 1 H), 7.13-7.28 (m, 5 H),7.65 (ddd, J = 0.0, 4.0, 8.0 Hz,5H), 7.76 (dd, J = 1.0, 12.0 Hz,1 H), 7.96 (dt, J = 1.0, 8.0 Hz,1 H),8.14 (d, J = 1.0 Hz, 1 H),8.31 (d, J = 4.0 Hz, 1 H), 8.34 (d,J = 12.0Hz, 1 H) 1-124

(DMSO-d6-300)1.60 (dd, J = 5.7,9.8 Hz, 1 H),2.04 (dd, J = 5.7,8.6 Hz, 1H),2.76 (dd, J = 8.6, 9.8 Hz, 1 H),7.14-7.30(m, 5 H), 7.45 (d,J = 3.4Hz, 1 H), 7.46 (d, J = 3.7 Hz,1 H), 7.48 (d, J = 3.0 Hz, 1 H),7.60 (d, J= 3.8 Hz, 1 H), 7.63 (dd,J = 3.4, 6.0 Hz, 1 H),7.72 (dd,J = 3.8, 6.0 Hz,1 H), 9.21(s,1 H), 12.22 (s, 1 H) 1-125

(DMSO-d6-300)1.60 (dd, J = 6.0, 9.4 Hz, 1 H),2.05 (dd, J = 5.6, 8.7 Hz,1 H),2.77 (dd, J = 8.7, 9.4 Hz, 1 H),7.15-7.31 (m, 5 H), 7.49 (d,J = 3.8Hz, 1 H), 7.56 (dd, J = 2.2,8.3 Hz, 1 H), 7.61 (d, J = 4.2 Hz,1 H), 7.75(d, J = 8.3 Hz, 1 H),7.82 (d, J = 1.9 Hz, 1 H),9.23 (s,1 H), 12.23 (s, 1H)

TABLE 1-26 Example Structural formula NMR 1-126

(CDCL3-300)1.89 (dd, J = 6.0, 9.0 Hz, 1 H),2.17 (dd, J = 6.0, 9.0 Hz, 1H),3.02 (t, J = 9.0 Hz, 1 H), 3.30 (t,J = 7.5 Hz, 2 H), 3.45-3.54 (m,2H), 5.46 (br, 1 H), 6.45 (br,1 H), 7.14-7.27 (m, 7 H),7.41 (d, J = 9.0Hz, 1 H),7.51 (dd, J = 3.0, 6.0 Hz, 1 H) 1-127

(DMSO-d6-300)1.77 (dd, J = 9.6, 5.6 Hz, 1 H),2.06 (dd, J = 8.8, 5.1 Hz,1 H),2.78 (t, J = 8.8 Hz, 1 H), 7.49-7.61 (m, 5 H), 7.63-7.69 (m,1 H),7.72-7.78 (m, 3 H), 8.01-8.08 (m, 2 H) 1-128

(DMSO-d6-300)1.52 (dd, J = 9.5, 5.5 Hz, 1 H),1.80 (dd, J = 8.4, 5.1 Hz,1 H),2.42-2.50 (m, 1 H), 6.28-6.41 (m, 3 H), 6.81 (t, J = 7.7 Hz,1 H),7.45-7.54 (m, 5 H), 7.68-7.74 (m, 2 H) 1-129

(DMSO-d6-400)1.54 (dd, J = 9.7, 5.0 Hz, 1 H),1.78 (dd, J = 8.7, 5.0 Hz,1 H),2.40 (t, J = 9.0 Hz, 1 H), 4.20 (d,J = 5.6 Hz, 1 H), 6.05 (t,J =6.0 Hz, 1 H), 6.32 (dd, J = 8.1,1.9 Hz, 1 H), 6.37 (d, J = 7.7 Hz,1 H),6.46-6.49 (m, 1 H),6.83 (t, J = 7.8 Hz, 1 H),7.29(dd, J = 7.7, 4.9 Hz,1H),7.45-7.53(m, 4H), 7.66-7.73 (m, 3 H), 8.39 (dd, J = 4.9,1.6 Hz, 1H), 8.52 (d, J = 2.1 Hz,1 H) 1-130

(DMSO-d6-300)1.69 (dd, J = 6.0, 12.0 Hz, 1 H),1.81 (dd, J = 6.0, 9.0 Hz,1 H),2.44 (t, J = 9.0 Hz, 1 H), 2.94 (s,3 H), 6.93 (brd, J = 9.0 Hz, 1H),6.96 (brd, J = 9.0 Hz, 1 H),7.09 (d, J = 6.0 Hz, 1 H), 7.13 (d,J =9.0 Hz, 1 H), 7.52 (d,J = 9.0 Hz, 2 H), 7.55 (d,J = 3.0 Hz, 1 H), 7.62(d,J = 3.0 Hz, 1 H), 7.75 (d,J = 9.0 Hz, 2 H)

TABLE 1-27 Example Structural formula NMR 1-131

(CDCL3-300)1.62 (dd, J = 6.0, 9.0 Hz, 1 H),2.00 (dd, J = 6.0, 9.0 Hz, 1H),2.71 (t, J = 9.0 Hz, 1 H), 7.14-7.27 (m, 5 H), 7.59 (d, J = 3.0 Hz,1H), 7.85 (d, J = 3.0 Hz, 1 H),8.04 (dd, J = 238494.0, 9.0 Hz,1 H), 8.09(d, J = 6.0 Hz, 1 H),8.64 (d, J = 3.0 Hz, 1 H),12.20 (brs, 1 H) 1-132

(DMSO-d6-300)1.63 (dd, J = 3.0, 9.0 Hz, 1 H),1.97 (dd, J = 6.0, 9.0 Hz,1 H),2.75 (t, J = 9.0 Hz, 1 H), 7.05-7.13 (m, 3 H), 7.26 (t, J = 7.5Hz,1 H), 7.53 (d, J = 9.0 Hz, 2 H),7.57 (s, 2 H), 7.76 (d, J = 9.0 Hz,2H), 9.22 (s, 1 H), 11.85 (brs,1 H), 12.27 (brs, 1 H) 1-133

(DMSO-d6-300)1.58 (dd, J = 6.0, 9.0 Hz, 1 H),1.99 (dd, J = 6.0, 9.0 Hz,1 H),2.70 (t, J = 9.0 Hz, 1 H), 6.60-6.76 (m, 3 H), 7.10 (t, J = 9.0Hz,1 H), 7.53 (d, J = 9.0 Hz, 2 H),7.56 (d, J = 3.0 Hz, 1 H), 7.58 (d,J= 3.0 Hz, 1 H), 7.76 (d, J = 9.0 Hz,2 H), 9.17 (s, 1 H) 1-134

(CDCL3-300)2.03 (dd, J = 6.0, 9.0 Hz, 1 H),2.09-2.17 (m, 1 H), 2.88 (t,J= 9.0 Hz, 1 H), 4.48 (s, 2 H),6.46 (brs, 1 H), 7.07-7.28 (m,5 H), 7.37(d, J = 9.0 Hz, 2 H),7.50 (d, J = 9.0 Hz, 2 H), 7.56 (d,J = 6.0 Hz, 1 H)1-135

(DMSO-d6-300)1.58 (dd, J = 6.0, 9.0 Hz, 1 H),1.94 (dd, J = 6.0, 9.0 Hz,1 H),2.70 (t, J = 9.0 Hz, 1 H),5.81 (brs, 2 H), 6.75 (d,J = 6.0 Hz, 1H), 7.08 (t, J = 7.5 Hz,1 H), 7.22-7.31 (m, 2 H), 7.49-7.58 (m, 4 H),7.76 (d, J = 9.0 Hz,2 H), 8.52 (brs, 1 H), 9.20 (brs,1 H)

TABLE 1-28 Example Structural formula NMR 1-136

(DMSO-d6-300)1.58 (dd, J = 6.0, 9.0 Hz, 1 H),1.90 (dd, J = 6.0, 9.0 Hz,1 H),2.69 (t, J = 9.0 Hz, 1 H), 6.87 (d,J = 6.0 Hz, 1 H), 6.94 (d, J =6.0 Hz,1 H), 7.09 (s, 1 H), 7.12 (t,J = 6.0 Hz, 1 H), 7.53 (d, J = 9.0Hz,2 H), 7.54-7.59 (m, 3 H), 7.76 (d,J = 9.0 Hz, 2 H), 8.05 (dt, J =9.0,6.0 Hz, 1 H), 8.76 (dd, J = 1.0,6.0 Hz, 1 H), 8.87 (d, J = 1.0 Hz,1H), 9.21 (s, 1 H), 10.41 (s, 1 H) 1-137

(METHANOL-d4-300)1.77-1.86 (m, 1 H), 2.13 (dd,J = 6.0, 9.0 Hz, 1 H),2.71 (t,J = 10.5 Hz, 1 H), 7.25-7.52 (m,5 H), 7.58-7.76 (m, 5 H) 1-138

(DMSO-d6-300)0.84 (dd, J = 6.0, 12.0 Hz, 1 H),0.99 (dd, J = 6.0, 9.0 Hz,1 H),2.64 (t, J = 9.0 Hz, 1 H), 3.73-3.82 (m, 2 H), 3.85-4.03 (m, 2H),4.75 (br, 1 H), 6.82 (t, J = 7.5 Hz,1 H), 6.90 (d, J = 9.0 Hz, 1H),7.04 (d, J = 9.0 Hz, 1 H), 7.15 (t,J = 9.0 Hz, 1 H), 7.53 (brd,J =9.0 Hz, 2 H), 7.57 (d, J = 6.0 Hz,1 H), 7.59 (d, J = 3.0 Hz, 1 H),7.76(brd, J = 9.0 Hz, 2 H),8.82 (br, 1 H), 11.95 (br, 1 H) 1-139

(DMSO-d6-300)0.88 (dd, J = 6.0, 9.0 Hz, 1 H),1.00 (dd, J = 6.0, 9.0 Hz,1 H),2.64 (t, J = 9.0 Hz, 1 H), 2.64 (t,J = 9.0 Hz, 1 H), 4.56 (d,J =15.0 Hz, 1 H), 4.66 (d,J = 15.0 Hz, 1 H), 6.79-6.89 (m,2 H), 7.02-7.09(m, 1 H), 7.10-7.20 (m, 1 H), 7.49-7.60 (m, 4 H),7.71-7.78 (m, 2 H),8.69(brs,1 H), 11.90 (brs, 1 H),12.83 (brs, 1 H) 1-140

(ACETONE-d6-400)0.92 (dd, J = 4.0, 8.0 Hz, 1 H),1.04 (dd, J = 8.0, 12.0Hz, 1 H),2.83 (t, J = 10.0 Hz, 1 H),7.11 (dt, J = 8.0, 2.0 Hz, 1H),7.16-7.28 (m, 7 H), 7.40-7.46 (m,3 H), 7.57 (t, J = 8.0 Hz, 1 H),7.62(dt, J = 10.0, 1.0 Hz, 1 H),7.80 (br, 1 H)

TABLE 1-29 Example Structural formula NMR 1-141

(ACETONE-d6-400)0.92 (dd, J = 8.0, 12.0 Hz, 1 H),1.05 (dd, J = 4.0, 8.0Hz, 1 H),2.84 (t, J = 10.0 Hz, 1 H), 7.13-7.28 (m, 9 H), 7.41 (t, J =2.0 Hz,1 H), 7.57 (t, J = 8.0 Hz, 1 H),7.62 (dt, J = 8.0, 2.0 Hz, 1H),7.78 (br, 1 H) 1-142

(ACETONE-d6-400)0.93 (dd, J = 4.0, 8.0 Hz, 1 H),1.05 (dd, J = 4.0, 8.0Hz, 1 H),2.85 (t, J = 10.0 Hz, 1 H), 7.12 (d,J = 8.0 Hz, 2 H), 7.16-7.30(m,6 H), 7.41-7.46 (m, 3 H), 7.59 (t,J = 8.0 Hz, 1 H), 7.67 (d, J = 8.0Hz,1 H), 7.82 (br, 1 H) 1-143

(ACETONE-d6-400)0.93 (dd, J = 4.0, 8.0 Hz, 1 H),1.06 (dd, J = 4.0, 8.0Hz, 1 H),2.86 (t, J = 10.0 Hz, 1 H),7.08 (dd, J = 4.0, 8.0 Hz, 1H),7.16-7.28 (m, 4 H), 7.34-7.37 (m,2 H), 7.52 (t, J = 2.0 Hz, 1 H),7.59(d, J = 8.0 Hz, 1 H), 7.62 (t,J = 8.0 Hz, 1 H), 7.70 (dt, J = 8.0,2.0Hz,1 H), 7.86 (brs, 1 H) 1-144

(METHANOL-d4-400)0.97 (dd, J = 4.0, 8.0 Hz, 1 H),1.05 (dd, J = 4.0, 8.0Hz, 1 H),2.78 (t, J = 10.0 Hz, 1 H), 3.15-3.25 (m, 4 H), 3.33-3.42 (m, 4H),6.94 (d, J = 8.0 Hz, 2 H), 7.15-7.29 (m, 7 H), 8.38 (brs, 1 H) 1-145

(DMSO-d6-300)1.68 (dd, J = 6.0, 9.0 Hz, 1 H),1.98-2.08 (m, 1 H),2.68-2.80 (m,1 H), 4.35 (ddd, J = 6.0, 15.0,27.0 Hz, 1 H), 4.54 (dd, J =15.0,21.0 Hz, 2 H), 6.78-6.93 (m, 2 H),7.03-7.32 (m, 7 H), 7.48-7.62(m,4 H), 7.74 (d, J = 9.0 Hz, 2 H),8.32 (brs, 1 H), 9.08 (brs, 1H),12.22 (brs, 1 H)

TABLE 1-30 Example Structural formula NMR 1-146

(DMSO-d6-300)1.76 (dd, J = 6.0, 12.0 Hz, 1 H),1.96-2.08 (m, 1 H),2.55-2.67 (m,1 H), 3.40-3.68 (m, 4 H),4.75 (dd, J = 15.0, 45.0 Hz, 2H),6.78-6.94 (m, 2 H), 7.05 (d,J = 6.0 Hz, 1 H), 7.15 (t, J = 9.0 Hz,1H), 7.47-7.62 (m, 4 H), 7.75 (d,J = 6.0 Hz, 2 H), 8.90 (brs, 1H),12.02(brs, 1 H) 1-147

(DMSO-d6-300)1.10 (d, J = 6.0 Hz, 3 H), 1.15 (d,J = 6.0 Hz, 3 H),1.55-1.66 (m,1 H), 1.91-2.02 (m, 1 H), 2.60-2.75 (m, 1 H), 3.92-4.05 (m,1 H),4.36 (d, J = 15.0 Hz, 1 H), 4.47 (d,J = 15.0 Hz, 1 H), 6.80-6.89(m,2 H), 7.04-7.08 (m, 1 H), 7.13-7.20 (m, 1 H), 7.53 (d, J = 9.0 Hz,2H), 7.57 (d, J = 6.0 Hz, 1 H),7.60 (d, J = 6.0 Hz, 1 H),7.76 (d,J = 9.0Hz, 2 H) 1-148

(ACETONE-d6-300)1.94 (dd, J = 6.0, 9.0 Hz, 1 H),2.17 (dd, J = 6.0, 9.0Hz, 1 H),2.92 (t, J = 9.0 Hz, 1 H), 4.11 (s,3 H), 7.15-7.33 (m, 6 H),7.63 (d,J = 6.0 Hz, 1 H), 7.70 (d, J = 6.0 Hz,1 H), 8.15 (d, J = 9.0 Hz,1 H) 1-149

(DMSO-d6-400)1.38-1.41 (m, 1 H), 1.39 (s, 3 H),2.09 (d, J = 5.3 Hz, 1H), 7.11 (m,5 H), 7.49-7.57 (m, 4 H), 7.71-7.76 (m, 2 H), 9.19 (brs, 1H),12.11 (brs, 1 H).

TABLE 2 Ex- am- ple Structural formula NMR 2

(DMSO-d6-400)1.41(s, 9H), 1.55(dd, J = 9.7,5.1 Hz, 1H), 1.94(dd, J =8.3,5.6 Hz, 1H), 2.40-2.47(m, 2H),2.62(t, J = 9.0 Hz, 1H), 3.48-3.55(m,2H), 3.94-4.02(m, 2H),6.26(brs, 1H), 7.43(d, J = 3.7 Hz,1H),7.11-7.24(m, 5H), 7.43(d,J = 3.7 Hz, 1H) 2-2

(DMSO-d6-400)1.53(dd, J = 10.2, 5.6 Hz, 1H),1.97-2.02(m, 1H), 2.66(brs,2H),2.71(t, J = 9.3 Hz, 1H), 3.26-3.32(m, 2H), 3.73(brs, 2H),6.27(brs,1H), 7.14-7.27(m, 6H),7.48(d, J = 4.2 Hz, 1H), 9.18(brs,2H) 2-3

(DMSO-d6-400)1.60(dd, J = 9.3, 5.6 Hz, 1H),1.84(dd, J = 8.3, 5.1 Hz,1H), 2.43-2.50(m, 3H), 3.56(t, J = 5.8 Hz,2H), 3.62(s, 3H), 4.03(brs,2H),6.26(brs, 1H), 7.21-7.07(m, 6H),7.44(d, J = 3.7 Hz, 1H) 2-4

(DMSO-d6-300)1.26(d, J = 6.8 Hz, 3H), 2.00(dq,J = 10.5, 6.8 Hz, 1H),2.79(d,J = 10.5 Hz, 1H), 4.24(s, 1H), 7.13-7.17(m, 5H), 7.38(d, J = 4.1Hz,1H), 7.51(d, J = 4.1 Hz, 1H),7.98(s, 1H), 8.91(s, 1H),9.06(brs, 1H),12.29(brs, 1H) 2-5

(CDCl3-400)1.33(d, J = 6.6 Hz, 3H), 2.18(brs,1H), 3.10(d, J = 10.8 Hz,1H),3.31(brs, 4H), 3.69(brs, 4H),6.65(d, J = 9.0 Hz, 1H), 7.21-7.28(m,5H), 7.66(dd, J = 2.3,9.0 Hz, 1H), 8.37(s, 1H) 2-6

(DMSO-d6-400)1.40(s, 3H), 1.43(d, J = 5.6 Hz,1H), 2.12(d, J = 5.6 Hz,1H), 7.13-7.26(m, 5H), 7.68(d, J = 3.7 Hz,1H), 7.85(d, J = 3.7 Hz,1H),8.17(s, 1H), 9.41(brs, 1H),12.14(brs, 1H) 2-7

(DMSO-d6-300)1.27(d, J = 6.8 Hz, 3H), 2.00(dd,J = 10.2, 6.4 Hz, 1H),2.79(d,J = 10.2, 1H), 7.09-7.35(m, 5H),7.70(d, J = 3.8 Hz, 1H), 7.85(d,J= 3.8 Hz, 1H), 8.17(s, 1H),9.28(brs, 0H), 12.34(brs, 1H) 2-8

(DMSO-d6-400)1.45-1.59(m, 2H), 1.68-1.84(m,3H), 2.44(dd, J = 13.0, 6.0Hz, 1H),2.69(d, J = 9.3 Hz, 1H), 3.00(td,J = 13.0, 5.6 Hz, 1H),6.95-7.10(m,4H), 7.48-7.61(m, 4H), 7.70-7.76(m, 2H) 2-9

(MeOH-d4-300)1.37(d, J = 9.0 Hz, 3H), 2.06(t,J = 18.0 Hz, 3H),2.15-2.27(m, 1H),2.94(d, J = 9.0 Hz, 1H), 7.16-7.28(m, 6H), 7.61(d, J =3.0 Hz,1H), 7.64(d, J = 3.0 Hz, 1H) 2-10

(CD3CN-400)2.32(dd, J = 7.4, 17.5 Hz, 1H),3.08(d, J = 10.4 Hz, 1H),3.79(dd,J = 7.2, 11.4 Hz, 1H), 3.96(dd,J = 7.6, 11.3 Hz, 1H),7.16-7.29(m,5H), 7.44(brs, 1H), 7.57-7.61(m,1H), 7.68-7.72(m, 1H) 2-11

(DMSO-d6-300)1.27(d, J = 6.8 Hz, 3H), 1.95-2.05(m, 1H), 2.86(d, J = 10.5Hz,1H), 3.05-3.15(m, 4H), 3.44-3.58(m, 4H), 6.93(t, J = 7.9 Hz,1H),7.15-7.30(m, 8H), 7.44(d,J = 7.9 Hz, 2H), 8.28(s, 1H),8.59(s, 1H),12.37(s, 1H) 2-12

(DMSO-d6-300)1.39(d, J = 3.4 Hz, 3H), 1.40(d,J = 3.4 Hz, 1H), 2.06(d, J= 6.4 Hz,1H), 5.56(brs, 2H), 6.89(dd,J = 8.3, 2.3 Hz, 1H), 7.09(d,J =2.3 Hz, 1H), 7.12-7.27(m, 6H),7.37(d, J = 4.1 Hz, 1H), 7.50(d,J = 4.1Hz, 1H), 9.13(brs, 1H),12.02(brs, 1H) 2-13

(DMSO-d6-300)2.03(dd, J = 6.8, 7.2 Hz, 1H),2.60(d, J = 6.8 Hz, 1H),2.99(dd,J = 17.3, 7.2 Hz, 1H), 3.21-3.36(m,1H), 5.25(s, 2H),6.98-7.09(m,3H), 7.13-7.19(m, 1H), 7.22(d,J = 8.7 Hz, 2H), 7.49(dd, J =8.3,2.3 Hz, 1H), 7.64(d, J = 8.3 Hz, 1H),7.71(d, J = 2.3 Hz, 1H),7.81(d,J = 8.7 Hz, 2H), 8.26(brs, 1H),8.40(s, 1H), 9.87(s, 1H) 2-14

(MeOH-d4-400)1.95-2.01(m, 1H), 2.08-2.16(m,1H), 2.69-2.76(m, 1H),4.03(s,3H), 6.88(s, 1H), 7.12-7.28(m,5H), 7.36(d, J = 3.9 Hz,1H),7.65(dd, J = 3.9 Hz, 1H), 8.45(s, 1H) 2-15

(MeOH-d4-400)1.19-1.35(m, 1H), 1.88-1.94(m,1H), 2.08-2.14(m, 1H),2.77-2.83(m, 1H), 3.86-3.94(m, 1H),4.22-4.32(m, 1H), 4.86-4.97(m,2H),6.81(d, J = 8.6 Hz, 1H), 7.14-7.32(m, 8H), 8.39(s, 1H) 2-16

(MeOH-d4-400)1.18-1.25(m, 1H), 1.90(dd, J = 9.4,5.5 Hz, 1H), 2.12(dd, J= 9.4,5.5 Hz, 1H), 2.77(t, J = 9.4 Hz, 1H),4.01(s, 3H), 7.12-7.28(m,6H),7.39(d, J = 3.9 Hz, 1H), 7.55(d,J = 3.9 Hz, 1H), 8.37(s, 1H) 2-17

(MeOH-d4-400)1.93(dd, J = 9.4, 5.5 Hz, 1H),2.13(dd, J = 9.4, 5.5 Hz,1H),2.78(t, J = 9.4 Hz, 1H), 7.12-7.28(m, 5H), 7.34(d, J = 9.4 Hz,2H),7.41(d, J = 3.9 Hz, 1H),7.59(d, J = 3.9 Hz, 1H), 7.77(d,J = 9.4 Hz, 2H),8.39(s, 1H) 2-18

(CDCl3-400)2.00-2.07(m, 1H), 2.11-2.13(m,1H), 2.90-2.96(m, 1H),6.29(brs,1H), 7.10-7.85(m, 10H) 2-19

(CDCl3-400)1.25-1.52(m, 2H), 2.11(m, 1H),2.87(t, J = 9.3 Hz, 1H),6.75(d,J = 8.7 Hz, 1H), 7.14-7.26(m, 5H),7.59-7.73(m, 6H) 2-20

(CDCl3-400)2.00-2.02(m, 2H), 2.40(s, 3H),2.89(t, J = 9.4 Hz, 1H),5.89(brs,1H), 7.03-7.26(m, 8H), 7.44-7.48(m, 3H) 2-21

(CDCl3-400)1.98-2.06(m, 2H), 2.90(t, J = 9.3 Hz,1H), 6.11(brs, 1H),7.06-7.26(m,8H), 7.49-7.55(m, 3H) 2-22

(DMSO-d6-300)1.67(dd, J = 9.8, 5.7 Hz, 1H),2.01(dd, J = 8.7, 5.7 Hz,1H),2.71(dd, J = 9.4, 4.7 Hz, 1H), 5.23(d,J = 13.2 Hz, 1H), 5.28(d, J =13.2 Hz,1H), 6.83(t, J = 7.2 Hz, 1H), 6.93(d,J = 7.5 Hz, 1H), 7.07(d, J= 7.5 Hz,1H), 7.13(t, J = 7.9 Hz, 1H), 7.50-7.61(m, 5H), 7.76(d, J = 8.7Hz, 2H),8.13(d, J = 7.9 Hz, 1H), 8.60(dd, J =5.3, 1.5 Hz, 1H), 8.81(d, J= 1.5 Hz,1H), 9.01(s, 1H), 12.03-12.29(m, 1H) 2-23

(DMSO-d6-300)1.72(dd, J = 9.4, 5.7 Hz, 1H),2.06(dd, J = 8.9, 5.8 Hz,1H),2.79(dd, J = 9.2, 4.6 Hz, 1H), 5.32(d,J = 14.3 Hz, 1H), 5.44(d, J =14.3 Hz,1H), 6.88(t, J = 7.3 Hz, 1H), 6.95(d,J = 7.9 Hz, 1H), 7.10(d, J= 7.5 Hz,1H), 7.16(t, J = 7.9 Hz, 1H),7.53(d, J = 8.3 Hz, 2H), 7.59(s,2H),7.67-7.73(m, 1H), 7.76(d, J = 8.7 Hz,1H), 7.88(d, J = 8.3 Hz,1H),8.20(t, J = 7.7 Hz, 1H), 8.79(d, J =5.3 Hz, 1H), 9.28(s, 1H) 2-24

(DMSO-d6-300)1.70-1.79(m, 1H), 1.90-1.99(m, 1H),6.74(d, J = 7.2 Hz, 1H),7.04(d,J = 6.8 Hz, 1H), 7.20-7.33(m, 3H),7.49-7.54(m, 5H), 7.71-7.74(m,3H),8.31-8.32(m, 2H) 2-25

(DMSO-d6-300)1.23(s, 7H), 1.25(s, 7H), 1.63(dd,J = 9.8, 5.7 Hz, 1H),1.99(dd, J = 9.0,5.7 Hz, 1H), 2.67(t, J = 10.2 Hz, 1H),3.67(dd, J =16.0, 9.2 Hz, 2H),4.62(brs, 1H), 6.79(t, J = 7.5 Hz,1H), 6.86(d, J = 7.9Hz, 1H), 7.01(d,J = 7.2 Hz, 1H), 7.13(t, J = 7.9 Hz, 1H),7.50-7.54(m,2H), 7.57(dd, J = 5.7,3.8 Hz, 2H), 7.74(dd, J = 6.6, 2.1 Hz,2H),8.75(brs, 1H) 2-26

(DMSO-d6-300)1.61(dd, J = 5.1, 2.6 Hz, 1H),2.01(dd, J = 8.7, 5.7 Hz,1H),2.48(s, 3H), 2.73(t, J = 9.0 Hz,1H), 7.14-7.26(m, 5H), 7.53(dd,J =5.8, 4.0 Hz, 2H), 7.58-7.58(m,1H), 12.20(brs, 1H) 2-27

(DMSO-d6-300)1.59-1.67(m, 1H), 1.95-2.03(m,1H), 2.64-2.74(m, 1H),7.13-7.25(m, 5H), 7.60(s, 1H), 7.62(d,J = 4.5 Hz, 1H), 7.69(d, J = 3.8Hz,1H), 8.20(dd, J = 8.3, 2.6 Hz, 1H),8.81(d, J = 2.6 Hz, 1H) 2-28

(MeOH-d4-400)1.96(dd, J = 5.4, 9.6 Hz, 1H), 2.10-2.15(m, 1H), 2.80(t, J= 9.0 Hz,1H), 3.25-3.45(m, 8H), 7.09(d,J = 7.6 Hz, 1H), 7.15-7.30(m,7H),7.40(t, J = 7.9 Hz, 1H) 2-29

(MeOH-d4-400)1.83-2.19(m, 2H), 2.70-2.84(m,1H), 3.06-3.53(m, 8H),7.06-7.50(m, 9H) 2-30

(MeOH-d4-400)1.96(dd, J = 5.6, 9.8 Hz, 1H),2.13(dd, J = 5.8, 8.5 Hz,1H),2.80(t, J = 9.1 Hz, 1H), 3.25-3.34(m,4H), 3.34-3.44(m, 4H),7.14-7.29(m, 7H), 7.40(d, J = 7.4 Hz, 1H) 2-31

(MeOH-d4-400)1.95(dd, J = 5.6, 9.8 Hz, 1H),2.12(dd, J = 5.8, 8.3 Hz,1H),2.79(t, J = 9.1 Hz, 1H), 3.20-3.42(m, 8H), 6.81(d, J = 8.6 Hz,1H),6.88(d, J = 8.6 Hz, 1H),6.95(s, 1H), 7.15-7.29(m, 6H) 2-32

(DMSO-d6-300)1.61(dd, J = 9.6, 5.8 Hz, 1H), 1.99-2.01(m, 1H), 2.73(t, J= 8.9 Hz,1H), 4.31(d, J = 5.3 Hz, 2H), 7.11-7.56(m, 10H), 7.73(d, J =8.7 Hz,2H), 7.94(d, J = 4.9 Hz, 1H),8.00(d, J = 2.6 Hz, 1H), 9.17(s, 1H)2-33

(Aceton-d6-300)1.94(dd, J = 6.0, 9.0 Hz, 1H),2.17(dd, J = 6.0, 9.0 Hz,1H),2.92(t, J = 9.0 Hz, 1H), 4.11(s,3H), 7.15-7.33(m, 6H), 7.63(d,J =6.0 Hz, 1H), 7.70(d, J = 6.0 Hz,1H), 8.15(d, J = 9.0 Hz, 1H) 2-34

(DMSO-d6-300)1.62(dd, J = 9.8, 5.7 Hz, 1H),2.02(dd, J = 8.7, 5.7 Hz,1H),2.74(t, J = 9.2 Hz, 1H), 7.17-7.27(m, 5H), 7.54-7.55(m, 2H),7.63(d,J = 4.1 Hz, 1H), 7.98(d,J = 3.8 Hz, 1H), 9.31(brs, 1H),12.23(brs, 1H)2-35

(DMSO-d6-300)1.56-1.57(m, 1H), 2.00(dd,J = 11.7, 6.0 Hz, 1H), 2.72(t,J =8.9 Hz, 1H), 3.58(d, J = 18.5 Hz,1H), 3.96(d, J = 18.5 Hz, 1H),7.19-7.25(m, 5H), 7.49(d, J = 4.1 Hz,1H), 7.59(d, J = 4.1 Hz, 1H) 2-36

(DMSO-d6-300)1.61(dd, J = 9.9, 5.1 Hz, 1H),1.91(dd, J = 8.3, 5.3 Hz,1H),2.59(t, J = 9.0 Hz, 1H), 5.00(s,2H), 6.74-6.87(m, 3H), 7.11(t,J =7.9 Hz, 1H), 7.26-7.44(m, 5H),7.46-7.57(m, 4H), 7.73(d,J = 8.4 Hz, 2H)2-37

(DMSO-d6-400)1.60(dd, J = 10.2, 4.6 Hz, 1H),1.81(dd, J = 8.3, 4.6 Hz,1H),2.42(t, J = 9.3 Hz, 1H), 2.88(s,3H), 4.50(s, 2H), 6.47-6.52(m,2H),6.67(s, 1H), 6.94(t,J = 7.9 Hz, 1H), 7.29(dd, J = 7.7,4.9 Hz, 1H),7.47-7.59(m, 5H),7.72(d, J = 8.8 Hz, 2H), 8.40-8.45(m, 2H) 2-38

(DMSO-d6-400)1.19-1.26(m, 1H), 1.24-1.25(m,2H), 1.36-1.49(m, 2H),7.09-7.25(m, 5H), 7.45-7.54(m, 4H),7.72(d, J = 8.3 Hz, 2H) 2-39

(DMSO-d6-300)1.61(dd, J = 9.6, 5.5 Hz, 1H), 1.95-2.04(m, 1H), 2.47(s,3H), 2.69(t,J = 9.6 Hz, 1H), 6.83(d, J = 2.6 Hz,1H), 7.12-7.29(m, 7H),7.47(d,J = 3.8 Hz, 1H), 12.22(brs, 1H) 2-40

(DMSO-d6-300)1.65-1.80(m, 2H), 2.37(s, 3H),7.09-7.22(m, 4H),7.22-7.31(m,4H), 7.51-7.56(m, 4H), 7.75(d,J = 10.0 Hz, 2H) 2-41

(DMSO-d6-300)0.67-1.68(m, 13H), 7.46-7.56(m,4H), 7.73(d, J = 7.2 Hz, 2H)2-42

(DMSO-d6-300)1.18(s, 6H), 1.61(dd, J = 9.8,5.7 Hz, 1H), 2.00(dd, J =8.5,5.7 Hz, 1H), 2.71(dd, J = 9.8,8.5 Hz, 1H), 3.63(s, 2H),4.61(brs,1H), 6.72-6.82(m, 3H),7.14(dd, J = 7.9, 7.9 Hz, 1H),7.52(d, J = 8.7 Hz,2H), 7.56(d,J = 3.8 Hz, 1H), 7.58(d, J = 3.8 Hz,1H), 7.75(d, J = 8.7 Hz,2H),9.17(s, 1H), 12.23(s, 1H) 2-43

(DMSO-d6-300)1.61-1.63(m, 1H), 2.04(dd, J = 8.8,5.5 Hz, 1H), 2.76(t, J =8.8 Hz, 1H),7.19-7.24(m, 5H), 7.69(d,J = 4.0 Hz, 1H), 7.85(d, J = 4.0Hz,1H), 8.16(s, 1H), 9.39(brs, 1H),12.22(brs, 1H) 2-44

(DMSO-d6-300)1.63(dd, J = 6.0, 9.0 Hz, 1H),2.04(dd, J = 6.0, 9.0 Hz,1H),2.75(t, J = 9.0 Hz, 1H), 7.10-7.27(m, 5H), 7.70(d, J = 3.0 Hz,1H),7.94(d, J = 3.0 Hz, 1H) 2-45

(DMSO-d6-300)1.62(dd, J = 6.0, 9.0 Hz, 1H),2.03(dd, J = 6.0, 9.0 Hz,1H),2.75(t, J = 9.0 Hz, 1H), 7.11-7.27(m, 5H), 7.70(d, J = 3.0 Hz,1H),7.94(d, J = 3.0 Hz, 1H) 2-46

(CDCl3-300)1.73(dd, J = 6.0, 9.0 Hz, 1H), 1.99-2.05(m, 1H), 2.33(q, J =9.0 Hz,1H), 5.14(d, J = 9.0 Hz, 1H),5.30(d, J = 18.0 Hz, 1H),5.50-5.59(m, 1H), 5.63(brs, 1H),7.20(d, J = 3.0 Hz, 1H), 7.41(d,J = 9.0Hz, 2H), 7.49-7.56(m, 3H) 2-47

(MeOH-d4-300)1.62-1.75(m, 2H), 2.18-2.34(m,1H), 4.67(dd, J = 6.0 , 12.0Hz, 1H),4.74-4.84(m, 1H), 7.33(d,J = 3.0 Hz, 1H), 7.40-7.47(m,3H),7.63(d, J = 9.0 Hz, 2H), 7.89(t,J = 7.5 Hz, 1H), 8.04(t, J = 7.5Hz,1H), 8.15(d, J = 9.0 Hz, 1H),8.32(d, J = 9.0 Hz, 1H) 2-48

(CDCl3-300)0.92(t, J = 7.5 Hz, 3H), 1.36-1.70(m, 4H), 1.79(dd, J =6.0,9.0 Hz, 1H), 5.59(brs, 1H),7.21(d, J = 3.0 Hz, 1H), 7.37-7.44(m,2H), 7.50-7.57(m, 3H) 2-49

(DMSO-d6-300)1.59(dd, J = 5.3, 2.6 Hz, 1H),1.98(dd, J = 8.7, 5.7 Hz,1H), 2.79-2.86(m, 1H), 2.87(s, 3H), 3.51-3.70(m, 2H), 4.14-4.24(m,1H),4.34-4.45(m, 1H), 6.87(t,J = 7.3 Hz, 1H), 6.95(d, J = 7.9 Hz,1H),7.07(d, J = 7.2 Hz, 1H),7.20(t, J = 7.7 Hz, 1H), 7.54(d,J = 8.7 Hz, 2H),7.61(d, J = 4.1 Hz,1H), 7.62(d, J = 4.1 Hz, 1H),7.76(d, J = 8.7 Hz, 2H)2-50

(DMSO-d6-300)1.59(dd, J = 9.8, 5.5 Hz, 1H),2.01(dd, J = 8.5, 5.5 Hz,1H), 2.66-2.77(m, 1H), 2.70(s, 3H), 7.14-7.30(m, 5H), 7.53(d, J = 3.8Hz,1H), 7.55(d, J = 3.8 Hz, 1H),8.05(s, 1H), 9.13(s, 1H),12.17(s, 1H)2-51

(DMSO-d6-300)1.62(dd, J = 10.0, 6.5 Hz, 1H),2.03(dd, J = 10.0, 6.5 Hz,2H),2.65(s, 3H), 2.75(t, J = 10.0 Hz,1H), 7.12-7.28(m, 5H), 7.63(d,J =3.8 Hz, 1H), 7.75(d, J = 10.0 Hz,1H), 9.34(brs, 1H), 12.20(brs,1H) 2-52

(CDCl3-300)1.65(dd, J = 6.0, 9.0 Hz, 1H), 1.89-1.98(m, 1H), 2.10-2.26(m,1H),3.85-3.96(m, 1H), 4.26(dd, J = 6.0,9.0 Hz, 1H), 5.80(brs,1H),6.82(d, J = 9.0 Hz, 2H), 6.93(t,J = 7.5 Hz, 1H), 7.16(d, J = 6.0Hz,1H), 7.20-7.28(m, 2H), 7.39(d,J = 9.0 Hz, 2H), 7.51(d, J = 9.0Hz,2H), 7.55(d, J = 6.0 Hz, 1H) 2-53

(DMSO-d6-300)1.38(s, 9H), 1.59(dd, J = 9.6,5.5 Hz, 1H), 2.00(dd, J =8.5,5.8 Hz, 1H), 2.84(dd, J = 9.4,4.7 Hz, 1H), 3.33-3.53(m,2H),4.09-4.21(m, 1H), 4.21-4.32(m,1H), 6.88(t, J = 7.5 Hz, 1H),6.95(d, J= 7.9 Hz, 1H), 7.08(d,J = 7.5 Hz, 1H), 7.21(t, J = 7.5 Hz,1H), 7.54(d, J= 8.7 Hz, 2H),7.60(s, 2H), 7.76(d, J = 8.7 Hz,2H), 8.44-8.74(m, 1H),8.83-9.24(m, 1H), 12.31(brs, 1H) 2-54

(DMSO-d6-300)1.26(s, 6H), 1.58(dd, J = 9.8,5.7 Hz, 1H), 2.01(dd, J =8.7,5.3 Hz, 1H), 2.74(t, J = 9.2 Hz, 1H),4.13(s, 2H), 7.17-7.27(m,5H),7.51(d, J = 3.8 Hz, 1H), 7.53(d,J = 4.1 Hz, 1H), 9.32(brs,1H),12.20(brs, 1H) 2-55

(DMSO-d6-300)1.61(dd, J = 9.8, 5.7 Hz, 1H),2.03(dd, J = 8.7, 5.7 Hz,1H),2.68(s, 3H), 2.75(dd, J = 9.8,8.7 Hz, 1H), 7.14-7.30(m, 5H),7.33(d,J = 4.1 Hz, 1H), 7.52(d,J = 4.1 Hz, 1H), 8.02(s, 1H),9.22(s, 1H),12.22(s, 1H) 2-56

(DMSO-d6-300)1.61(dd, J = 8.9, 5.8 Hz, 1H),1.99(dd, J = 8.9, 5.8 Hz,1H),2.69(d, J = 8.9 Hz, 1H), 5.25(s,2H), 6.24(t, J = 2.1 Hz, 1H),6.98(d,J = 7.5 Hz, 1H), 7.10-7.23(m, 3H), 7.43(d, J = 1.5 Hz,1H), 7.56(d, J =3.8 Hz, 1H),7.72(d, J = 1.9 Hz, 1H), 7.83(d,J = 3.8 Hz, 1H),8.01-8.10(m, 2H),8.62(d, J = 1.5 Hz, 1H), 9.20(s,1H), 12.20(brs, 1H)2-57

(DMSO-d6-300)1.62(dd, J = 9.0, 5.7 Hz, 1H),2.00(dd, J = 9.0, 5.7 Hz,1H),2.71(t, J = 9.0 Hz, 1H), 3.24(s,3H), 4.33(s, 2H), 7.06-7.24(m,4H),7.56(d, J = 3.8 Hz, 1H),7.83(d, J = 4.1 Hz, 1H), 8.00-8.10(m, 2H),8.62(d, J = 2.3 Hz,1H), 9.18(brs, 1H), 12.17(brs,1H) 2-58

(DMSO-d6-300)1.13(m, 1H), 1.26(q, J = 4.8 Hz,1H), 1.46(d, J = 7.9 Hz,1H), 1.66-1.86(m, 5H), 1.91-2.06(m, 1H),2.15-2.27(m, 1H),7.45-7.55(m,4H), 7.73(d, J = 8.7 Hz, 2H),8.78(brs, 1H), 12.33(brs, 2H)2-59

(DMSO-d6-300)0.87-0.90(m, 6H), 1.15-1.23(m,3H), 1.37-1.40(m, 1H),7.48-7.54(m, 4H), 7.73(dd, J = 6.8,1.9 Hz, 2H), 8.89(s, 1H), 12.52(s,1H)2-60

(CDCl3-300)2.04-2.16(m, 2H), 2.95(t,J = 9.6 Hz, 1H), 6.11(brs,1H),7.11-7.29(m, 5H), 7.39(d,J = 4.1 Hz, 1H), 7.51(d, J = 3.8 Hz,1H),7.79(s, 1H) 2-61

(CDCl3-300)1.17-1.37(m, 2H), 1.42-1.84(m,10H), 5.63(brs, 1H), 7.20(d,J =6.0 Hz, 1H), 7.41(d, J = 9.0 Hz,2H), 7.49-7.58(m, 3H) 2-62

(CDCl3-300)0.92(s, 9H), 1.49(t, J = 9.0 Hz,1H), 1.62-1.73(m, 2H),5.70(brs,1H), 7.22(d, J = 3.0 Hz, 1H),7.41(d, J = 9.0 Hz, 2H),7.51-7.57(m, 3H) 2-63

(DMSO-d6-300)1.67(dd, J = 9.6, 5.8 Hz, 1H),2.09(dd, J = 8.5, 5.8 Hz,1H),2.66(t, J = 9.0 Hz, 1H), 4.52(d,J = 14.7 Hz, 1H), 4.73(d, J = 14.7Hz,1H), 5.05(brs, 1H), 7.04(d,J = 7.2 Hz, 1H), 7.11(t, J = 7.3 Hz,1H),7.19(t, J = 7.5 Hz, 1H),7.37(d, J = 6.8 Hz, 1H), 7.53(d,J = 8.7 Hz, 2H),7.58(q, J = 3.8 Hz,2H), 7.76(d, J = 8.7 Hz, 2H),9.25(brs, 1H),12.17(brs, 1H) 2-64

(acetone-d6-400)1.58-2.04(m, 2H), 2.51-3.47(complexm, 12H),6.81-7.41(m,9H) 2-65

(DMSO-d6-400)1.60(dd, J = 5.5, 9.7 Hz, 1H),2.01(dd, J = 5.6, 8.6 Hz,1H),2.72(t, J = 9.2 Hz, 1H), 6.83(d,J = 8.7 Hz, 2H), 7.16-7.33(m,7H),7.47-7.54(m, 3H), 9.09(bs, 1H),9.87(bs, 1H), 12.2(bs, 1H) 2-66

(MeOH-d4-400)1.89(dd, J = 5.8, 9.8 Hz, 1H),2.14(dd, J = 5.8, 8.6 Hz,1H),2.57(s, 3H), 2.83(t, J = 9.2 Hz,1H), 7.15-7.27(m, 5H), 7.61(d,J =4.0 Hz, 1H), 7.77(d, J = 4.0 Hz,1H) 2-67

(MeOH-d4-400)1.96(dd, J = 5.4, 9.5 Hz, 1H),2.06(dd, J = 6.0, 8.2 Hz,1H), 2.53-2.57(m, 1H), 3.10-3.19(m, 4H),3.34-3.49(m, 4H),6.93-6.99(m,4H), 7.10-7.28(m, 5H) 2-68

(MeOH-d4-400)1.96(dd, J = 5.7, 9.8 Hz, 1H),2.12(dd, J = 5.7, 8.5 Hz,1H), 2.75-2.79(m, 1H), 3.12-3.41(m, 4H),3.46-3.83(m, 4H), 6.91(d,J = 9.1Hz, 1H), 7.15-7.29(m, 5H),7.73(dd, J = 2.5, 9.0 Hz, 1H),8.34(s, 1H) 2-69

(DMSO-d6-300)1.67(q, J = 5.1 Hz, 1H), 2.06(q,J = 5.1 Hz, 1H),2.69-3.60(m, 11H),7.15-7.31(m, 4H), 7.51-7.61(m,4H), 7.72-7.79(m, 2H),9.13(brs,1H), 12.31(brs, 1H) 2-70

(MeOH-d4-300)2.14(dd, J = 6.0, 9.0 Hz, 1H),2.31(dd, J = 6.0, 9.0 Hz,1H),3.18(t, J = 9.0 Hz, 1H), 7.38-7.46(m, 3H), 7.61(d, J = 6.0 Hz,1H),7.66(d, J = 9.0 Hz, 2H),8.04(t, J = 6.0 Hz, 1H), 8.63(d,J = 6.0 Hz, 1H),8.73(d, J = 6.0 Hz,1H), 8.80(s, 1H) 2-71

(DMSO-d6-300)1.46-1.76(m, 1H), 1.77-2.00(m,1H), 2.65-2.75(m, 4H),2.95-3.43(m, 5H), 3.53-3.64(m, 2H),7.12-7.28(m, 3H), 7.53-7.57(m,4H),7.72-7.78(m, 3H), 8.97(brs,1H), 12.41(brs, 1H) 2-72

(DMSO-d6-300)1.69(dd, J = 5.1, 2.6 Hz, 1H),1.87(dd, J = 8.9, 5.8 Hz,1H),2.96(t, J = 9.0 Hz, 1H), 3.28-3.31(m, 2H), 3.53-3.55(m,2H),4.98(brs, 1H), 7.20-7.34(m, 5H),7.53-7.57(m, 4H), 7.75-7.76(m,2H),8.10(t, J = 5.7 Hz, 1H),8.85(brs, 1H), 12.31(brs, 1H) 2-73

(DMSO-d6-300)1.66(dd, J = 9.6, 5.8 Hz, 1H),2.08(dd, J = 8.5, 6.2 Hz,1H),2.81(t, J = 8.9 Hz, 1H), 3.49-3.64(m, 8H), 7.22-7.33(m,4H),7.49-7.59(m, 4H), 7.76(d,J = 8.7 Hz, 2H), 9.20(brs, 1H),12.30(brs,1H) 2-74

(DMSO-d6-300)1.30(s, 6H), 1.68(dd, J = 9.0,5.7 Hz, 1H), 2.08(dd, J =8.1,7.0 Hz, 1H), 2.80(t, J = 9.0 Hz, 1H),3.49(d, J = 6.0 Hz, 2H),4.92(t,J = 6.2 Hz, 1H), 7.29-7.35(m, 2H),7.40-7.80(m, 9H), 9.22(brs,1H),12.25 (brs, 1H) 2-75

(DMSO-d6-300)1.67(dd, J = 9.8, 5.7 Hz, 1H),2.09(dd, J = 8.3, 5.7 Hz,1H),2.80(t, J = 9.4 Hz, 1H), 3.30(t,J = 5.8 Hz, 2H), 3.49(brt, J = 5.7Hz,2H), 4.71(brs, 1H), 7.30-7.36(m,2H), 7.50-7.59(m, 4H), 7.65-7.78(m,4H), 8.37(t, J = 5.1 Hz,1H), 9.23(brs, 1H), 12.25(brs,1H) 2-76

(DMSO-d6-300)1.25(brs, 1H), 1.97(brs, 1H),2.73(brs, 1H), 3.40-3.64(m,8H),7.14-7.30(m, 4H), 7.52(d,J = 8.7 Hz, 2H), 7.58(s, 2H),7.76(d, J =8.7 Hz, 2H) 2-77

(DMSO-d6-300)1.33(s, 3H), 1.37(s, 3H),1.75(dd, J = 5.0, 2.5 Hz,1H),2.03(dd, J = 9.0, 5.7 Hz, 1H),3.00(t, J = 9.4 Hz, 1H), 4.02-4.15(m,2H), 7.28-7.33(m, 2H),7.53(d, J = 8.7 Hz, 2H), 7.60-7.61(m, 2H),7.74-7.76(m, 4H) 2-78

(DMSO-d6-300)1.28(s, 3H), 1.29(s, 3H),1.63(dd, J = 5.1, 2.6 Hz,1H),1.89(dd, J = 8.5, 5.5 Hz, 1H), 2.75-2.88(m, 1H), 3.48(d, J = 10.9Hz,1H), 3.55(d, J = 10.5 Hz, 1H), 7.14-7.27(m, 4H), 7.55(dt, J =12.4,4.8 Hz, 4H), 7.75(d, J = 8.7 Hz, 2H) 2-79

(DMSO-d6-300)1.61(dd, J = 8.9, 6.0 Hz, 1H),2.00(dd, J = 8.3, 6.0 Hz,1H),2.48(s, 3H), 2.70(dd, J = 8.9,8.3 Hz, 1H), 7.13-7.28(m, 5H),7.39(d,J = 4.1 Hz, 1H), 7.56(d,J = 4.1 Hz, 1H), 7.58(s, 1H) 2-80

(MeOH-d4-400)1.78-1.84(m, 1H), 2.05-2.08(m,1H), 2.63(s, 3H), 2.71(t,J =8.7 Hz, 1H), 7.12-7.24(m, 5H),7.99(d, J = 8.3 Hz, 2H), 8.11(d,J = 8.1Hz, 2H) 2-81

(MeOH-d4-400)1.86(dd, J = 5.8, 9.9 Hz, 1H),2.13(dd, J = 5.8, 8.7 Hz,1H),2.83(t, J = 9.3 Hz, 1H), 7.14-7.26(m, 5H), 7.57-7.70(m,5H),7.98-8.02(m, 2H) 2-82

(MeOH-d4-400)1.90(dd, J = 5.8, 9.8 Hz, 1H),2.12(dd, J = 5.8, 8.7 Hz,1H),2.81(t, J = 9.2 Hz, 1H), 7.02(d,J = 4.0 Hz, 1H), 7.14-7.27(m,5H),7.43(d, J = 4.1 Hz, 1H) 2-83

(MeOH-d4-400)1.83(dd, J = 5.7, 9.8 Hz, 1H),2.09(dd, J = 5.7, 8.6 Hz,1H),2.78(t, J = 9.2 Hz, 1H), 7.09-7.26(m, 6H), 7.62(dd, J = 1.3,3.7 Hz,1H), 7.75(dd, J = 1.3,5.0 Hz, 1H) 2-84

(DMSO-d6-300)1.61-1.73(m, 1H), 1.92-2.02(m,1H), 2.12(t, J = 19.2 Hz,3H), 7.07-7.27(m, 5H), 7.67(d, J = 3.8 Hz,1H), 7.70(s, 1H), 7.80(d,J =3.8 Hz, 1H) 2-85

(DMSO-d6-300)1.60(dd, J = 9.6, 5.5 Hz, 1H),2.02(dd, J = 8.7, 5.7 Hz,1H),2.45(s, 3H), 2.74(t, J = 9.2 Hz,1H), 6.82(s, 1H), 7.16-7.25(m,5H),7.59(d, J = 4.0 Hz, 1H),7.64(d, J = 4.0 Hz, 1H), 9.28(s,1H), 12.20(brs,1H) 2-86

(DMSO-d6-300)1.69(dd, J = 9.6, 5.5 Hz, 1H),2.05(dd, J = 8.7, 5.3 Hz,1H),2.40(s, 3H), 2.79(t, J = 8.5 Hz,1H), 7.24-7.30(m, 2H), 7.35(t,J =9.0 Hz, 1H), 7.51(d, J = 9.0 Hz,2H), 7.56(s, 2H), 7.68-7.81(m,4H),9.21(s, 1H), 12.29(brs, 1H) 2-87

(DMSO-d6-300)1.55-1.63(m, 1H), 1.96-2.04(m,1H), 2.46(s, 3H),2.65-2.76(m,1H), 7.13-7.29(m, 6H), 7.38(d,J = 4.1 Hz, 1H), 7.54(d, J =4.1 Hz,1H), 8.55(s, 1H), 9.12(s, 1H),12.19(s, 1H) 2-88

(DMSO-d6-300)1.59(dd, J = 5.5, 9.2 Hz, 1H),2.02(dd, J = 9.2, 5.5 Hz,1H),2.47(s, 3H), 2.74(t, J = 9.2 Hz,1H), 7.15-7.30(m, 5H), 7.45(d,J =4.1 Hz, 1H), 7.59(d, J = 4.1 Hz,1H), 9.23(s, 1H), 12.19(s, 1H) 2-89

(DMSO-d6-300)1.71-1.74(m, 1H), 2.07(brs, 1H),2.11(s, 3H), 2.60-2.67(m,1H),3.26(s, 3H), 3.48-3.53(m, 3H),3.67(d, J = 13.2 Hz, 1H),7.08-77.20(m, 4H), 7.54-7.57(m, 4H),7.75(d, J = 9.0 Hz, 2H) 2-90

(DMSO-d6-300)0.94(t, J = 7.3 Hz, 3H), 1.63-1.69(m, 3H), 1.97-2.03(m,1H),2.69-2.79(m, 3H), 6.88(s, 1H),7.16-7.23(m, 5H), 7.60(d,J = 4.1 Hz,1H), 7.65(d, J = 4.1 Hz,1H), 12.19(brs, 1H) 2-91

(DMSO-d6-300)1.78-1.83(m, 1H), 1.93-1.98(m,1H), 2.35-2.39(m, 4H),2.66-2.70(m, 1H), 3.27(d, J = 12.1 Hz,1H), 3.48-3.57(m, 4H), 3.72(d,J =13.6 Hz, 1H), 7.02-7.09(m, 3H),7.17-7.20(m, 1H), 7.50(d,J = 8.3 Hz, 2H),7.55(s, 2H),7.73(d, J = 8.3 Hz, 2H) 2-92

(DMSO-d6-300)1.25(t, J = 7.7 Hz, 3H), 1.61(dd,J = 5.1, 2.6 Hz, 1H),2.01(dd,J = 8.7, 5.7 Hz, 1H), 2.72(t,J = 8.9 Hz, 1H), 2.80(q, J = 7.5Hz,1H), 6.88(s, 1H), 7.16-7.27(m,5H), 7.61(d, J = 3.8 Hz, 1H),7.66(d, J= 4.1 Hz, 1H), 12.23(brs,1H) 2-93

(MeOH-d4-400)0.95(t, J = 7.41 Hz, 3H), 1.57-1.66(m, 2H), 1.89(dd, J =5.6,9.6 Hz, 1H), 2.10(dd, J = 5.9,8.0 Hz, 1H), 2.72(t, J = 9.0 Hz,1H),3.28-3.30(m, 2H), 7.12-7.25(m,5H), 7.56(d, J = 3.9 Hz, 1H),7.59(d, J= 3.9 Hz, 1H) 2-94

(MeOH-d4-400)1.23(d, J = 6.6 Hz, 6H), 1.85-1.91(m, 1H), 2.09-2.13(m,1H),2.76(t, J = 7.9 Hz, 1H), 4.11-4.18(m, 1H), 7.12-7.27(m, 5H),7.55(s,1H), 7.63(s, 1H) 2-95

(MeOH-d4-400)1.52-2.17(m, 10H), 2.79(t,J = 9.3 Hz, 1H), 4.22-4.30(m,1H),7.12-7.28(m, 5H), 7.55(s, 1H),7.64(s, 1H), 2-96

(MeOH-d4-400)1.92(dd, J = 5.4, 9.2 Hz, 1H), 2.13-2.18(m, 1H), 2.81(t, J= 8.9 Hz,1H), 7.14-7.37(m, 8H), 7.61-7.66(m, 3H), 7.83(s, 1H) 2-97

(MeOH-d4-400)1.85-1.92(m, 1H), 2.09-2.15(m,1H), 2.43-2.54(m, 2H),2.78(t,J = 9.3 Hz, 1H), 3.59(t, J = 6.9 Hz,2H), 7.11-7.29(m, 5H),7.58(s,2H) 2-98

(CDCl3-300)2.15-2.17(m, 1H), 2.35-2.39(m,1H), 2.87(t, J = 9.4 Hz, 1H),5.35-5.46(m, 2H), 6.65(d, J = 2.3 Hz,1H), 7.20-7.26(m, 5H), 7.37(d,J =3.8 Hz, 1H), 7.61(d, J = 3.8 Hz,1H) 2-99

(DMSO-d6-300)1.62(dd, J = 9.8, 5.7 Hz, 1H), 1.99-2.02(m, 1H), 2.71(t, J= 8.9 Hz,1H), 7.31-7.43(m, 6H), 7.65(d,J = 4.1 Hz, 1H), 7.68(s,1H),7.82(d, J = 4.1 Hz, 1H) 2-100

(DMSO-d6-300)1.27(d, J = 5.1 Hz, 1H), 1.34(s,3H), 2.02(d, J = 5.1 Hz,1H),4.03(s, 2H), 7.12-7.19(m, 5H),7.62(dd, J = 8.3, 1.7 Hz, 1H),7.79(dd,J = 8.3, 1.7 Hz, 1H),7.86(s, 1H), 7.95-7.97(m, 2H),8.08(d, J = 8.3 Hz,1H), 8.86(s,1H), 11.91(s, 1H) 2-101

(DMSO-d6-400)1.38-1.42(m, 4H), 2.10(d,J = 5.6 Hz, 1H), 7.11-7.26(m,5H),7.49-7.60(m, 4H), 7.72-7.77(m,2H), 9.20(brs, 1H), 12.11(brs,1H)2-102

(CDCl3-300)2.10-2.15(m, 2H), 2.94(t,J = 9.4 Hz, 1H), 5.85(brs,1H),6.83(t, J = 55.8 Hz, 1H), 7.06(d,J = 3.8 Hz, 1H), 7.20(d, J = 47.5Hz,7H), 7.49(d, J = 4.1 Hz, 1H) 2-103

(MeOH-d4-400)1.80-1.84(m, 1H), 2.07-2.13(m,1H), 2.73(t, J = 8.6 Hz, 1H),7.09-7.26(m, 5H), 7.45(s, 1H), 7.51(s,1H) 2-104

(MeOH-d4-400)1.20(t, J = 7.24 Hz, 3H), 1.89(dd,J = 5.6, 9.8 Hz, 1H),2.12(dd,J = 5.8, 8.7 Hz, 1H), 2.80(t,J = 9.2 Hz, 1H), 3.37(q, J = 7.2Hz,2H), 7.13-7.27(m, 5H), 7.56(d,J = 4.0 Hz, 1H), 7.58(d, J = 4.0 Hz,1H)2-105

(MeOH-d4-400)0.60-0.64(m, 2H), 0.79(dt, J = 5.0,7.1 Hz, 2H), 1.89(dd, J= 5.7,9.8 Hz, 1H), 2.10(dd, J = 5.6,8.7 Hz, 1H), 2.74(t, J = 9.1 Hz,1H),2.77-2.84(m, 1H), 7.12-7.25(m,5H), 7.54(d, J = 4.0 Hz, 1H),7.56(d, J= 4.0 Hz, 1H) 2-106

(MeOH-d4-400)1.91(dd, J = 5.8, 9.8 Hz, 1H), 2.12-2.18(m, 1H), 2.84(t, J= 9.3 Hz,1H), 4.05(dd, J = 9.8, 18.9 Hz, 2H),7.15-7.27(m, 5H), 7.59(d,J= 4.0 Hz, 1H), 7.67(d, J = 4.0 Hz,1H) 2-107

(DMSO-d6-300)1.39(s, 3H), 1.42(d, J = 5.7 Hz,1H), 2.06-2.19(m, 1H),2.11(t,J = 10.2 Hz, 3H), 7.08-7.12(m, 3H),7.24(t, J = 7.3 Hz, 2H),7.65(d,J = 3.8 Hz, 1H), 7.71(s, 1H),7.80(d, J = 4.1 Hz, 1H),9.37(brs,1H), 12.12(brs, 1H) 2-108

(MeOH-d4-300)1.92(dd, J = 9.8, 5.7 Hz, 1H),1.98(s, 3H), 2.11(dd, J =8.7,5.7 Hz, 1H), 2.75(t, J = 9.2 Hz, 1H),2.86(t, J = 7.0 Hz, 2H),4.20(t,J = 7.0 Hz, 2H), 7.02-7.06(m, 1H),7.08-7.18(m, 3H),7.36-7.45(m,3H), 7.58(d, J = 3.8 Hz, 1H),7.66(d, J = 8.3 Hz, 2H) 2-109

(MeOH-d4-300)1.92(dd, J = 9.8, 5.7 Hz, 1H), 2.08-2.13(m, 1H),2.71-2.78(m, 3H),3.69(t, J = 6.8 Hz, 2H), 7.03(d,J = 6.0 Hz, 1H),7.07-7.18(m, 3H),7.36-7.45(m, 3H), 7.58(dd, J = 4.1,0.4 Hz, 1H),7.62-7.68(m, 2H) 2-110

(DMSO-d6-300)1.62(dd, J = 9.8, 5.7 Hz, 1H), 1.98-1.99(m, 1H), 2.68(t, J= 8.9 Hz,1H), 3.34(s, 3H), 4.59(s, 2H),7.16-7.23(m, 6H), 7.60(d,J = 4.1Hz, 1H), 7.71(d, J = 4.1 Hz,1H) 2-111

(DMSO-d6-300)1.63(dd, J = 8.5, 5.8 Hz, 1H),2.03(dd, J = 8.5, 5.8 Hz,1H),2.75(t, J = 8.5 Hz, 1H), 6.55(s,1H), 7.18-7.28(m, 5H), 7.70(d,J =4.1 Hz, 1H), 7.89(d, J = 4.1 Hz,1H), 8.28(s, 1H) 2-112

(DMSO-d6-300)1.39(s, 3H), 1.42(d, J = 5.7 Hz,1H), 2.11(d, J = 5.7 Hz,1H), 7.12-7.28(m, 5H), 7.68(d, J = 3.8 Hz,1H), 7.89(d, J = 3.8 Hz,1H),8.28(s, 1H), 9.42(s, 1H),12.13(s, 1H) 2-113

(DMSO-d6-300)1.66(dd, J = 9.8, 5.7 Hz, 1H),2.06(dd, J = 8.5, 5.5 Hz,1H),2.78(t, J = 9.4 Hz, 1H), 7.20-7.30(m, 5H), 7.41-7.43(m, 2H),7.47(d,J = 4.1 Hz, 1H), 7.57(d,J = 3.8 Hz, 1H), 7.87-7.89(m, 2H),8.00-8.02(m,1H), 9.29(brs, 1H),12.26(brs, 1H) 2-114

(DMSO-d6-300)1.66(dd, J = 9.8, 5.7 Hz, 1H),2.05(dd, J = 8.5, 5.8 Hz,1H),2.677(t, J = 9.4 Hz, 1H), 7.19-7.27(m, 5H), 7.56-7.64(m,3H),7.68-7.69(m, 2H), 7.74(d,J = 3.8 Hz, 1H), 7.91-7.93(m,2H),12.27(brs, 1H) 2-115

(DMSO-d6-400)1.64(dd, J = 10.2, 5.8 Hz, 1H),2.04(dd, J = 8.6, 5.8 Hz,1H),2.76(t, J = 9.3 Hz, 1H), 6.03(d,J = 45.5 Hz, 2H), 7.14-7.28(m,5H),7.61(d, J = 4.2 Hz, 1H), 7.82(d,J = 4.2 Hz, 1H), 9.35(brs,1H),12.20(brs, 1H) 2-116

(acetone-d6-400)1.15(t, J = 7.3 Hz, 3H), 1.92(dd,J = 5.7, 9.8 Hz, 1H),2.16(dd,J = 5.7, 8.7 Hz, 1H), 2.91(t,J = 9.3 Hz, 1H), 3.03(q, J = 7.3Hz,2H), 7.16-7.29(m, 5H), 8.01(s,1H), 8.41(s, 1H) 2-117

(acetone-d6-400)0.98(t, J = 7.4 Hz, 3H),1.72(sextet, J = 7.3 Hz,2H),1.91(dd, J = 5.7, 9.8 Hz, 1H),2.16(dd, J = 5.8, 8.7 Hz, 1H),2.91(t,J = 9.3 Hz, 1H), 2.98(t,J = 7.2 Hz, 2H), 7.16-7.29(m, 5H),8.03(s, 1H),8.42(s, 1H) 2-118

(DMSO-d6-300)1.65(dd, J = 5.1, 2.6 Hz, 1H),2.05(dd, J = 8.3, 5.7 Hz,1H),2.77(t, J = 9.2 Hz, 1H), 7.20-7.27(m, 5H), 7.48-7.53(m, 3H),7.65(d,J = 3.8 Hz, 1H), 8.11(d,J = 7.9 Hz, 2H), 8.17(s, 1H),9.23(brs, 1H),12.25(brs, 1H) 2-119

(CDCl3-300)2.05-2.16(m, 2H), 2.92(t,J = 9.0 Hz, 1H), 6.11(brs,1H),6.99(t, J = 54.0 Hz, 1H), 7.12-7.28(m, 5H), 7.36(d, J = 3.0 Hz,1H),7.57(d, J = 3.0 Hz, 1H),7.64(s, 1H) 2-120

(DMSO-d6-400)1.63(dd, J = 9.7, 5.6 Hz, 1H),2.03(dd, J = 8.6, 5.8 Hz,1H),2.74(t, J = 9.3 Hz, 1H), 5.83(d,J = 46.8 Hz, 2H), 7.15-7.28(m,5H),7.59(d, J = 4.2 Hz, 1H), 7.73(d,J = 4.2 Hz, 1H), 8.03(d, J = 2.3Hz,1H), 9.27(brs, 1H), 12.20(brs,1H) 2-121

(DMSO-d6-400)1.39(s, 3H), 1.42(d, J = 5.6 Hz,1H), 2.10(d, J = 5.6 Hz,1H),5.83(d, J = 46.4 Hz, 2H), 7.10-7.27(m, 5H), 7.57(d, J = 3.7 Hz,1H),7.73(d, J = 3.7 Hz, 1H),8.03(d, J = 2.3 Hz, 1H), 9.27(brs,1H),12.11(brs, 1H) 2-122

(DMSO-d6-400)1.66(dd, J = 5.1, 2.6 Hz, 1H),2.04(dd, J = 8.3, 5.6 Hz,1H),2.74(t, J = 9.5 Hz, 1H), 7.14-7.27(m, 5H), 7.30(t, J = 7.9 Hz,1H),7.37(t, J = 7.9 Hz, 1H),7.50(s, 1H), 7.61(d, J = 3.7 Hz,1H),7.62-7.71(m, 3H), 12.27(brs,1H) 2-123

(MeOH-d4-300)0.85(d, J = 9.0 Hz, 3H), 0.92(d,J = 9.0 Hz, 3H),1.91-2.05(m, 1H),1.93(d, J = 6.0 Hz, 1H), 2.02(d,J = 6.0 Hz, 1H),7.09-7.24(m, 5H),7.36(d, J = 6.0 Hz, 1H), 7.42(d,J = 9.0 Hz, 2H),7.55(d, J = 6.0 Hz,1H), 7.64(d, J = 9.0 Hz, 2H) 2-124

(CDCl3-300)2.08(t, J = 18.0 Hz, 3H), 2.16-2.25(m, 2H), 2.92-3.01(m,1H),6.03(brs, 1H), 7.17-7.32(m, 5H),7.38(d, J = 3.0 Hz, 1H), 7.57(s,1H),7.62(d, J = 3.0 Hz, 1H) 2-125

(MeOH-d4-400)1.93(dd, J = 5.5, 9.7 Hz, 1H),2.11(dd, J = 5.7, 8.4 Hz,1H),2.77(t, J = 9.1 Hz, 1H), 2.83-2.86(m, 2H), 3.58-3.70(m, 2H),4.51(q,J = 15.2 Hz, 2H), 6.95-7.39(m, 9H) 2-126

(MeOH-d4-400)1.94-1.99(m, 1H), 2.14(dd, J = 5.8,8.4 Hz, 1H), 2.80(t, J =9.2 Hz, 1H),3.71-3.85(m, 2H), 4.23-4.25(m,2H), 4.70-4.79(m, 2H),7.12-7.75(m, 10H) 2-127

(MeOH-d4-400)1.97(dd, J = 5.6, 9.8 Hz, 1H),2.13(dd, J = 5.7, 8.5 Hz,1H),2.81(t, J = 9.1 Hz, 1H), 3.10(t,J = 5.6 Hz, 2H), 3.70(m, 2H),4.52(q,J = 15.9 Hz, 2H), 7.14-8.36(m, 10H), 8.60(s, 1H) 2-128

(MeOH-d4-400)1.76-1.86(m, 2H), 1.92-1.99(m,3H), 2.12(dd, J = 5.8, 8.5Hz, 1H),2.82(t, J = 9.1 Hz, 1H), 3.17-3.27(m, 2H), 3.43-3.52(m,2H),4.48(td, J = 3.2, 9.9 Hz, 1H), 6.90-6.94(m, 2H), 7.16-7.29(m, 7H)2-129

(MeOH-d4-400)0.71-0.80(m, 3H), 1.49-1.99(m,3H), 2.04-2.15(m, 1H),7.14-7.65(m, 11H) 2-130

(DMSO-d6-300)1.46(s, 6H), 1.61(dd, J = 9.8,5.7 Hz, 1H), 2.00-2.02(m,1H),2.71(t, J = 8.5 Hz, 1H), 5.64(brs,1H), 7.19-7.29(m, 6H), 7.47(d,J =3.8 Hz, 1H), 12.24(brs, 1H) 2-131

(DMSO-d6-300)1.36(s, 3H), 1.46(d, J = 4.5 Hz,1H), 2.03(d, J = 4.5 Hz,1H), 7.09-7.25(m, 6H), 7.56(d, J = 4.1 Hz,1H), 7.84(d, J = 3.4 Hz,1H),8.07(dd, J = 14.5, 8.5 Hz, 2H),8.65(s, 1H), 11.87(brs, 1H) 2-132

(DMSO-d6-300)1.30(s, 9H), 1.59(dd, J = 9.8,5.7 Hz, 1H), 2.02(dd, J =8.7,5.7 Hz, 1H), 2.74(t, J = 9.2 Hz, 1H),7.19-7.29(m, 5H), 7.44(d,J =3.8 Hz, 1H), 9.24(brs, 1H),12.22(brs, 1H) 2-133

(DMSO-d6-300)0.98(t, J = 7.3 Hz, 3H), 1.48-1.64(m, 3H), 1.88-2.05(m,1H),2.37-2.40(m, 2H), 2.60-2.76(m,1H), 7.11-7.29(m, 6H), 7.44(d,J = 4.1Hz, 1H), 12.23(brs, 1H) 2-134

(DMSO-d6-300)1.68(dd, J = 9.6, 5.5 Hz, 1H),1.95(dd, J = 6.8, 5.3 Hz,1H), 2.51-2.65(m, 1H), 7.09-7.34(m, 5H),7.52-7.81(m, 5H),7.93-8.08(m,2H), 12.38(brs, 1H) 2-135

(DMSO-d6-300)1.62(dd, J = 9.6, 5.5 Hz, 1H),2.02(dd, J = 8.5, 5.8 Hz,1H),2.74(t, J = 9.0 Hz, 1H), 6.59(t,J = 6.4 Hz, 1H), 6.68-6.78(m,2H),7.15-7.30(m, 5H), 7.34(d,J = 3.8 Hz, 1H), 7.41(d, J = 9.0 Hz,1H),7.52(d, J = 3.8 Hz, 1H),7.99(d, J = 1.1 Hz, 1H), 8.23(d,J = 6.8 Hz, 1H),9.11(brs, 1H),12.23(brs, 1H) 2-136

(DMSO-d6-300)1.72(dd, J = 8.9, 5.5 Hz, 1H),1.90(dd, J = 11.9, 5.5 Hz,1H),2.52-2.60(m, 1H), 7.11-7.22(m,2H), 7.26-7.38(m, 2H), 7.48-7.63(m,5H), 7.76(d, J = 8.7 Hz,2H), 12.19(brs, 1H) 2-137

(DMSO-d6-300)1.52(dd, J = 9.4, 5.7 Hz, 1H), 1.92-1.94(m, 1H),2.61-2.65(m, 1H),5.65(d, J = 47.1 Hz, 2H), 7.17-7.22(m, 5H), 7.38(d, J =3.4 Hz,1H), 7.93(d, J = 8.7 Hz, 2H),8.08(d, J = 8.7 Hz, 2H) 2-138

(CDCl3-300)1.42-1.52(m, 1H), 1.57-1.66(m,1H), 1.79-1.92(m, 1H),3.40-3.54(m, 2H), 4.33(s, 2H), 4.63-4.76(m, 1H), 6.54(brs, 1H),7.06(d, J= 3.8 Hz, 1H), 7.24(q,J = 45.2 Hz, 6H), 7.36(d, J = 8..7 Hz,2H), 7.43(d,J = 8.7 Hz, 2H) 2-139

(CDCl3-300)1.64-1.82(m, 2H), 1.92-2.04(m,1H), 3.23(dd, J = 8.7, 4.9 Hz,1H),3.52(dd, J = 8.9, 4.4 Hz, 1H),4.33(d, J = 14.7 Hz, 1H), 4.40(d,J =14.7 Hz, 1H), 4.57-4.69(m, 1H),7.14-7.36(m, 8H), 7.49(d,J = 7.9 Hz, 2H),7.64(d, J = 3.8 Hz,1H) 2-140

(CDCl3-300)2.06(dd, J = 6.0, 9.0 Hz, 1H),2.15(dd, J = 6.0, 9.0 Hz,1H),3.04(t, J = 9.0 Hz, 1H), 5.71(brs,1H), 6.80(d, J = 15.0 Hz, 1H),7.16-7.29(m, 5H), 7.36-7.46(m, 5H),7.52(d, J = 15.0 Hz, 1H) 2-141

(acetone-d6-400)1.90(dd, J = 9.2, 5.7 Hz, 1H),2.14(dd, J = 8.8, 5.7 Hz,1H),2.85(dd, J = 9.2, 8.8 Hz, 1H),4.07(s, 2H), 7.15-7.30(m,6H),7.44-7.48(m, 1H), 7.68(brs, 1H),7.92-7.96(m, 1H), 7.99-8.05(m,2H),8.07-8.11(m, 1H) 2-142

(acetone-d6-400)1.90(dd, J = 9.4, 5.3 Hz, 1H),2.14(dd, J = 8.8, 5.3 Hz,1H),2.85(dd, J = 9.4, 8.8 Hz, 1H),4.08(s, 2H), 7.15-7.32(m,6H),7.48-7.52(m, 1H), 7.72(s, 1H),7.94-8.08(m, 3H), 8.10-8.15(m,1H)2-143

(MeOH-d4-400)1.76-1.87(m, 2H), 1.85(dd, J = 5.7,9.8 Hz, 1H),1.99-2.06(m, 2H),2.10(dd, J = 5.7, 8.5 Hz, 1H),2.74(t, J = 9.1 Hz, 1H),3.16-3.30(m, 2H), 3.45-3.56(m, 2H),4.47-4.52(m, 1H), 6.89-6.94(m,3H),7.15-7.29(m, 7H) 2-144

(MeOH-d4-400)1.80-1.89(m, 2H), 1.95(dd, J = 5.7,9.8 Hz, 1H),2.00-2.09(m, 2H),2.13(dd, J = 5.7, 8.6 Hz, 1H),2.81(t, J = 9.2 Hz, 1H),3.20-3.30(m, 2H), 3.46-3.55(m, 2H),4.62(tt, J = 3.4, 7.0 Hz, 1H),7.08(d,J = 8.7 Hz, 2H), 7.16-7.29(m, 5H), 7.56(d, J = 8.7 Hz, 2H) 2-145

(MeOH-d4-400)1.75-1.85(m, 2H), 1.92-2.03(m,3H), 2.12(dd, J = 5.7, 8.6Hz, 1H),2.81(t, J = 9.2 Hz, 1H), 3.16-3.26(m, 2H), 3.44-3.52(m,2H),4.42(tt, 3.4, 7.0 Hz, 1H), 6.91-7.01(m, 4H), 7.16-7.29(m, 5H) 2-146

(MeOH-d4-400)0.69-0.78(m, 3H), 1.52-2.09(m,4H), 3.93-3.98(m, 2H),7.09-8.03(m, 11H) 2-147

(MeOH-d4-400)1.13(s, 3H), 1.25(s, 3H), 1.38-1.43(m, 1H), 1.51(d, J = 5.5Hz,1H), 7.38-7.69(m, 6H) 2-148

(MeOH-d4-400)1.94(dd, J = 5.6, 9.8 Hz, 1H),2.13(dd, J = 5.7, 8.5 Hz,1H), 2.58-2.66(m, 2H), 2.84(d, J = 9.2 Hz,1H), 3.42-3.55(m, 2H),3.93(dq,J = 3.0, 17.2 Hz, 2H), 6.10(s, 1H),7.15-7.43(m, 10H) 2-149

(MeOH-d4-400)1.94(dd, J = 5.6, 9.8 Hz, 1H),2.13(dd, J = 5.7, 8.5 Hz,1H),2.59(brs, 2H), 2.83(t, J = 9.2 Hz,1H), 3.42-3.55(m, 2H), 3.93(dq,J =3.1, 17.5 Hz, 2H), 6.14(s, 1H),7.15-7.42(m, 9H) 2-150

(DMSO-d6-300)1.72(dd, J = 8.9, 5.5 Hz, 1H),1.90(dd, J = 11.9, 5.5 Hz,1H),2.52-2.60(m, 1H), 7.11-7.22(m,2H), 7.26-7.38(m, 2H), 7.48-7.63(m,5H), 7.76(d, J = 8.7 Hz,2H), 12.19(brs, 1H) 2-151

(MeOH-d4-300)1.83(dd, J = 9.8, 5.7 Hz, 1H),2.07(dd, J = 8.5, 5.5 Hz,1H),2.75(t, J = 9.2 Hz, 1H), 7.10-7.18(m, 4H), 7.27(d, J = 7.5 Hz,2H),7.38-7.44(m, 3H), 7.57(d,J = 8.3 Hz, 2H) 2-152

(DMSO-d6-300)1.52(dd, J = 8.7, 5.7 Hz, 1H),1.96(dd, J = 8.7, 5.7 Hz,1H),2.67(t, J = 8.7 Hz, 1H), 7.18-7.22(m, 5H), 7.44(t, J = 52.7 Hz,1H),7.71(s, 1H), 7.94(d,J = 8.7 Hz, 2H), 8.13(d, J = 8.7 Hz,2H) 2-153

(CDCl3-400)1.99(dd, J = 9.5, 6.0 Hz, 1H),2.12(dd, J = 8.8, 6.0 Hz,1H),3.01(dd, J = 9.5, 8.8 Hz, 1H),5.86(brs, 1H), 6.79(d, J = 15.3Hz,1H), 7.14-7.23(m, 5H), 7.27-7.44(m, 5H) 2-154

(DMSO-d6-300)1.63-1.65(m, 1H), 1.70-1.88(m,4H), 1.89-2.01(m, 1H),2.62(t,J = 5.5 Hz, 2H), 2.73(t, J = 5.3 Hz,2H), 7.07-7.26(m, 5H),7.51(d,J = 4.1 Hz, 1H), 7.62(d, J = 4.1 Hz,1H) 2-155

(MeOH-d4-400)1.94(dd, J = 5.7, 9.8 Hz, 1H),2.11(dd, J = 5.7, 8.5 Hz,1H), 2.70-2.78(m, 1H), 3.11-3.30(m, 4H),3.84-3.86(m, 4H),7.12-7.28(m,5H), 8.35-8.40(m, 2H) 2-156

(MeOH-d4-400)1.93(dd, J = 5.5, 9.8 Hz, 1H),2.11(dd, J = 5.8, 8.2 Hz,1H),2.58(t, J = 7.7 Hz, 1H), 2.78(t,J = 9.1 Hz, 1H), 2.90(t, J = 7.7Hz,1H), 3.72-3.87(m, 1H), 4.11(t,J = 5.2 Hz, 2H), 6.23(s, 1H),7.06(dd, J= 2.0, 8.6 Hz, 1H), 7.13-7.27(m, 6H), 7.44(d, J = 1.9 Hz, 1H) 2-157

(MeOH-d4-400)1.96(dd, J = 5.7, 9.8 Hz, 1H),2.15(dd, J = 5.8, 8.6 Hz,1H),2.84(t, J = 9.2 Hz, 1H), 3.32-3.43(m, 4H), 3.66-3.68(m,4H),7.07-7.31(m, 7H), 7.48(d,J = 8.0 Hz, 1H), 7.64(d, J = 7.9 Hz,1H)2-158

(MeOH-d4-400)1.92(dd, J = 5.9, 9.9 Hz, 1H),2.14(dd, J = 5.8, 8.6 Hz,1H),2.59(t, J = 7.7 Hz, 1H), 3.19-3.58(m, 8H), 3.62(s, 2H), 7.14-7.55(m,10H) 2-159

(MeOH-d4-400)1.95(dd, J = 5.7, 9.8 Hz, 1H),2.13(dd, J = 5.8, 8.5 Hz,1H), 2.80-2.85(m, 1H), 3.26-3.38(m, 4H),3.49-3.79(m, 4H),7.16-7.29(m,5H), 7.41-7.49(m, 4H) 2-160

(MeOH-d4-400)1.95(dd, J = 5.7, 9.8 Hz, 1H),2.13(dd, J = 5.8, 8.6 Hz,1H), 2.80-2.86(m, 1H), 3.16-3.38(m, 4H),3.41-3.54(m, 2H),3.67-3.88(m,2H), 7.16-7.53(m, 9H) 2-161

(DMSO-d6-300)1.70(dd, J = 9.0, 5.7 Hz, 1H),2.02(dd, J = 8.7, 5.7 Hz,1H),2.81(dd, J = 9.0, 8.7 Hz, 1H), 7.13-7.28(m, 5H), 7.36(d, J = 15.4Hz,1H), 7.45(d, J = 15.4 Hz, 1H),7.78(d, J = 8.3 Hz, 2H), 7.92(d,J = 8.3Hz, 2H), 8.70(brs, 1H),12.39(brs, 1H) 2-162

(CDCl3-300)2.00(dd, J = 9.2, 5.3 Hz, 1H),2.15(dd, J = 9.0, 5.3 Hz,1H),3.03(dd, J = 9.2, 9.0 Hz, 1H),5.86(brs, 1H), 6.90(d, J = 15.4Hz,1H), 7.14-7.24(m, 5H), 7.47-7.56(m, 2H), 7.59-7.71(m, 3H) 2-163

(CDCl3-300)1.82-1.86(m, 1H), 2.00-2.04(m,1H), 2.17-2.30(m, 2H), 2.61(t,J= 7.9 Hz, 2H), 2.73(t, J = 8.9 Hz,1H), 3.86(t, J = 7.2 Hz, 2H),6.39(d, J= 4.1 Hz, 1H), 7.05-7.24(m, 5H), 7.37(d, J = 4.1 Hz,1H), 7.45(d, J = 4.1Hz, 1H) 2-164

(CDCl3-300)1.91-2.02(m, 9H), 3.76-3.78(m,2H), 6.51(d, J = 4.1 Hz, 1H),7.17-7.19(m, 5H), 7.38(d, J = 4.5 Hz,1H), 7.47(d, J = 4.1 Hz, 1H) 2-165

(DMSO-d6-300)1.45-1.47(m, 1H), 1.91(dd, J = 8.7,6.0 Hz, 1H),2.63-2.71(m, 1H),5.79(d, J = 4.1 Hz, 1H), 7.07(d,J = 4.1 Hz, 1H),7.20-7.22(m, 5H),8.48(s, 1H) 2-166

(CDCl3-300)0.98-1.20(m, 5H), 1.50-1.79(m,5H), 1.90-2.02(m, 2H),2.50-2.74(m, 2H), 3.85-4.09(m, 3H),6.91(brs, 1H), 7.09-7.24(m,6H),7.61(s, 1H), 7.75(d, J = 8.7 Hz, 1H) 2-167

(DMSO-d6-300)1.87(dd, J = 9.8, 5.7 Hz, 1H),2.09(dd, J = 8.9, 5.5 Hz,1H),2.66(t, J = 8.7 Hz, 1H), 7.17-7.27(m, 3H), 7.52-7.55(m, 3H),7.59(s,2H), 7.76(d, J = 8.7 Hz,2H), 9.07(brs, 1H), 12.31(brs,1H) 2-168

(DMSO-d6-300)1.87(dd, J = 9.8, 5.7 Hz, 1H),2.09(dd, J = 8.9, 5.5 Hz,1H),2.66(t, J = 8.7 Hz, 1H), 7.17-7.27(m, 3H), 7.52-7.55(m, 3H),7.59(s,2H), 7.76(d, J = 8.7 Hz,2H), 9.07(brs, 1H), 12.31(brs,1H) 2-169

(DMSO-d6-300)1.67(dd, J = 9.8, 5.7 Hz, 1H),2.03(dd, J = 7.5, 5.7 Hz,1H),2.73(t, J = 7.0 Hz, 1H), 7.19-7.25(m, 2H), 7.34-7.41(m, 2H),7.69(q,J = 3.6 Hz, 1H), 7.86(d,J = 3.8 Hz, 1H), 8.18(d, J = 1.1 Hz,1H),9.33(brs, 1H), 12.44(brs,1H) 2-170

(DMSO-d6-300)1.78(dd, J = 9.6, 5.5 Hz, 1H),2.01(dd, J = 7.7, 5.5 Hz,1H),2.71(t, J = 7.2 Hz, 1H), 7.43-7.54(m, 1H), 7.52(d, J = 8.7 Hz,2H),7.58(q, J = 3.9 Hz, 2H),7.65(d, J = 7.2 Hz, 1H), 7.75(d,J = 8.7 Hz, 2H),7.98-8.05(m, 2H),8.80(brs, 1H), 12.32(brs, 1H) 2-171

(DMSO-d6-300)1.64(dd, J = 9.6, 5.5 Hz, 1H), 1.99-2.02(m, 1H),2.67-2.72(m, 1H),7.17-7.22(m, 5H), 7.69(d,J = 3.8 Hz, 1H), 7.80(s,1H),7.83(d, J = 3.8 Hz, 1H) 2-172

(DMSO-d6-400)1.53(dd, J = 9.7, 5.6 Hz, 1H),1.98(dd, J = 8.3, 5.8 Hz,1H),2.70(t, J = 9.7 Hz, 1H), 2.71-2.76(m, 5H), 3.26-3.31(m,2H),3.67-3.76(m, 2H), 6.26(brs, 1H),7.16-7.25(m, 6H), 7.47(d,J = 4.2 Hz,1H), 9.16(brs, 1H),12.18(brs, 1H) 2-173

(DMSO-d6-300)1.51(dd, J = 9.6, 5.8 Hz, 1H),1.90(dd, J = 8.7, 5.7 Hz,1H),2.61(t, J = 9.2 Hz, 1H), 3.09-3.90(brs, 2H), 4.34(s, 2H),6.39-6.50(m, 3H), 6.93(t, J = 7.9 Hz,1H), 7.51-7.58(m, 4H), 7.65(t,J =6.4 Hz, 1H), 7.75(dt, J = 8.8,2.0 Hz, 2H), 8.07(d, J = 7.2 Hz,1H),8.60(d, J = 5.7 Hz, 1H), 8.69(s,1H), 9.16(s, 1H), 12.15(brs, 1H)2-174

(DMSO-d6-300)1.65-1.72(m, 2H), 2.17(t,J = 9.0 Hz, 1H), 4.72(brs,2H),6.29(t, J = 9.6 Hz, 2H), 6.39(s,1H), 6.75(t, J = 9.6 Hz, 1H),7.48-7.59(m, 4H), 7.75(d, J = 7.9 Hz,2H), 12.42(brs, 1H) 2-175

(DMSO-d6-300)1.68(q, J = 4.9 Hz, 1H), 2.06(dd,J = 8.5, 5.5 Hz, 1H),2.82(t,J = 9.2 Hz, 1H), 7.35-7.59(m, 6H),7.73-7.79(m, 3H), 7.86(s,1H),9.21(brs, 1H), 12.43(brs, 1H),12.93(brs, 1H) 2-176

(DMSO-d6-300)1.58(dd, J = 9.8, 5.7 Hz, 1H),1.98(dd, J = 8.7, 5.3 Hz,1H),2.69(t, J = 9.2 Hz, 1H), 2.86(s,6H), 6.65-6.69(m, 3H), 7.07(t,J =7.5 Hz, 1H), 7.51-7.59(m, 4H),7.76(d, J = 8.7 Hz, 1H), 9.18(s,1H),12.16(brs, 1H) 2-177

(DMSO-d6-300) (120C)1.64(dd, J = 9.2, 5.1 Hz, 1H),1.98(dd, J = 8.8, 5.1Hz, 1H),2.04(s, 3H), 2.50-2.54(m, 2H),2.74(t, J = 8.8 Hz, 1H),3.61-3.68(m, 2H), 4.10-4.15(m, 2H),6.23-6.29(m, 1H), 7.09(d,J = 3.7 Hz,1H), 7.12-7.27(m, 5H),7.46(d, J = 4.0 Hz, 1H) 2-178

(DMSO-d6-300)1.87(dd, J = 9.8, 5.7 Hz, 1H),2.09(dd, J = 8.9, 5.5 Hz,1H),2.66(t, J = 8.7, 1H), 7.17-7.27(m, 3H), 7.52-7.55(m, 3H),7.59(s,2H), 7.76(d, J = 8.7 Hz,2H), 9.07(brs, 1H), 12.31(brs,1H) 2-179

(DMSO-d6-300)1.64(dd, J = 9.8, 5.7 Hz, 1H),2.07(dd, J = 8.7, 5.3 Hz,1H), 2.47-2.53(m, 2H), 2.70(t, J = 9.4 Hz,1H), 2.83-2.85(m, 1H),2.98-3.08(m, 1H), 7.05-7.14(m, 4H),7.53(d, J = 8.3 Hz, 2H), 7.57(d,J =4.1 Hz, 1H), 7.60(d, J = 4.1 Hz,1H), 7.77(d, J = 8.3 Hz, 2H),12.16(brs,1H) 2-180

(DMSO-d6-300)1.61(dd, J = 5.1, 2.6 Hz, 1H),2.02(dd, J = 8.3, 5.7 Hz,1H), 2.46-22.50(m, 2H), 2.68-2.78(m, 3H),7.05-7.07(m, 3H),7.15-7.17(m,1H), 7.53(d, J = 8.7 Hz, 2H),7.56(d, J = 4.1 Hz, 1H),7.58(d,J = 4.1 Hz, 1H), 7.76(d, J = 8.7 Hz,2H), 9.19(brs, 1H),12.17(brs,1H) 2-181

(DMSO-d6-300)1.66(dd, J = 9.4, 3.8 Hz, 1H), 1.78-1.90(m, 1H), 2.33(t, J= 9.4 Hz,1H), 3.07(s, 2H), 6.82(d,J = 6.4 Hz, 1H), 6.89-7.06(m,3H),7.45-7.60(m, 4H), 7.74(d,J = 8.3 Hz, 2H) 2-182

(DMSO-d6-300)1.62(q, J = 4.8 Hz, 1H), 2.02(dd,J = 8.5, 5.5 Hz, 1H),2.74(t,J = 9.0 Hz, 1H), 4.44(s, 2H),5.16(brs, 1H), 7.04-7.23(m,4H),7.50-7.59(m, 4H), 7.76(d,J = 8.3 Hz, 2H), 9.21(brs, 1H),12.21(brs,1H) 2-183

(DMSO-d6-300)1.55(dd, J = 9.8, 5.7 Hz, 1H),1.95(dd, J = 8.7, 5.3 Hz,1H),2.66(t, J = 9.1 Hz, 1H), 2.94(s,3H), 4.54(s, 2H), 6.36-6.71(m,2H),6.93-7.07(m, 1H), 7.21-7.89(m, 9H), 8.44(s, 2H),9.17(brs, 1H),12.20(brs, 1H) 2-184

(DMSO-d6-300)1.71(dd, J = 10.0, 5.5 Hz, 1H),2.05(dd, J = 6.8, 5.3 Hz,1H),2.81(t, J = 6.4 Hz, 1H), 3.84(s,3H), 7.38-7.59(m, 6H), 7.74-7.80(m,3H), 7.86(s, 1H),9.25(brs, 1H), 12.32(brs, 1H) 2-185

(acetone-d6-400)1.76(dd, J = 5.6, 9.0 Hz, 1H), 2.12-2.16(m, 1H),2.73-2.77(m, 1H),3.15(d, J = 14.6 Hz, 1H), 3.39-3.42(m, 4H),3.82-3.85(m, 4H),4.30(dd, J = 0.9, 14.6 Hz, 1H),7.00(d, J = 9.1 Hz, 1H),7.16-7.32(m, 5H), 7.80(dd, J = 2.5,9.1 Hz, 1H), 8.43(s, 1H) 2-186

(acetone-d6-400)1.78(dd, J = 5.6, 9.0 Hz, 1H),2.15(dd, J = 6.5, 7.4 Hz,1H),2.77(t, J = 8.4 Hz, 1H), 3.19(d,J = 14.7 Hz, 1H), 3.45-3.48(m,4H),3.65-3.67(m, 4H), 4.34(d,J = 15.3 Hz, 1H), 7.17-7.46(m, 9H) 2-187

(acetone-d6-400)1.87(dd, J = 4.6, 7.2 Hz, 1H),2.05(td, J = 2.2, 4.4 Hz,1H), 2.54-2.58(m, 1H), 3.71(d, J = 11.5 Hz,1H), 4.02(d, J = 11.5 Hz,1H), 7.14-7.29(m, 5H), 7.49-7.80(m, 6H) 2-188

(DMSO-d6-300)1.62(dd, J = 5.0, 2.5 Hz, 1H),2.00(dd, J = 8.3, 6.0 Hz,1H),2.71(t, J = 8.9 Hz, 1H), 3.60(s,5H), 7.10(t, J = 7.5 Hz, 3H),7.20(t,J = 7.3 Hz, 1H), 7.46-7.60(m, 4H), 7.75(d, J = 8.7 Hz,2H), 9.17(brs,1H), 12.24(brs,1H) 2-189

(DMSO-d6-300)1.62(dd, J = 5.0, 2.5 Hz, 1H),1.98(dd, J = 8.3, 6.0 Hz,1H),2.69(t, J = 9.4 Hz, 1H), 2.81(s,3H), 2.93(s, 3H), 3.61(s,2H),7.05(t, J = 9.0 Hz, 3H), 7.17(t,J = 7.5 Hz, 1H), 7.47-7.60(m,4H),7.76(d, J = 8.7 Hz, 2H), 12.23(brs,1H) 2-190

(DMSO-d6-300)1.58-1.70(m, 1H), 1.87-1.99(m,1H), 2.54-2.67(m, 1H),3.24-3.56(m, 8H), 3.63(s, 2H), 6.94-7.10(m, 3H), 7.15(t, J = 7.0 Hz,1H),7.52(d, J = 8.7 Hz, 2H),7.56(s, 2H), 7.75(d, J = 8.3 Hz, 2H) 2-191

(DMSO-d6-300)1.63(q, J = 4.6 Hz, 1H), 1.92-2.02(m, 1H), 2.07-2.30(m,7H),2.61-2.75(m, 1H), 3.20-3.56(m,4H), 3.63(s, 2H), 6.98-7.11(m,3H),7.17(t, J = 7.5 Hz, 1H),7.52(d, J = 8.7 Hz, 2H), 7.57(s,2H), 7.76(d, J =8.3 Hz, 2H) 2-192

(DMSO-d6-300)1.62(dd, J = 9.8, 5.7 Hz, 1H),2.03(dd, J = 8.1, 5.5 Hz,1H),2.75(dd, J = 9.2, 4.6 Hz, 1H), 7.15-7.30(m, 5H), 7.53(d, J = 8.7Hz,2H), 7.56(d, J = 4.1 Hz, 1H),7.58(d, J = 4.1 Hz, 1H), 7.76(d,J = 8.7Hz, 2H), 9.21(brs, 1H),12.21(brs, 1H) 2-193

(DMSO-d6-300)1.89(dd, J = 9.6, 5.8 Hz, 1H),2.10(dd, J = 8.7, 5.3 Hz,1H),2.66(t, J = 11.3 Hz, 1H), 7.17-7.27(m, 3H), 7.54(d, J = 7.2 Hz,1H),7.72(d, J = 4.1 Hz, 1H),7.87(d, J = 3.8 Hz, 1H), 8.18(s,1H), 12.33(brs,1H) 2-194

(DMSO-d6-300)1.71-1.76(m, 1H), 2.07-2.10(m,1H), 2.59-2.64(m, 1H),3.43-3.59(m, 4H), 3.77(d, J = 17.0 Hz,1H), 3.84(d, J = 16.6 Hz, 1H),6.98-7.00(m, 1H), 7.07-7.15(m, 3H),7.53(d, J = 8.7 Hz, 2H), 7.57(d,J =3.8 Hz, 1H), 7.59(d, J = 3.8 Hz,1H), 7.76(d, J = 8.7 Hz, 2H),12.30(d, J= 10.0 Hz, 1H) 2-195

(DMSO-d6-300)1.71-1.76(m, 1H), 2.07-2.10(m,1H), 2.59-2.64(m, 1H),3.43-3.59(m, 4H), 3.77(d, J = 17.0 Hz,1H), 3.84(d, J = 16.6 Hz, 1H),6.98-7.00(m, 1H), 7.07-7.15(m, 3H),7.53(d, J = 8.7 Hz, 2H), 7.57(d,J =3.8 Hz, 1H), 7.59(d, J = 3.8 Hz,1H), 7.76(d, J = 8.7 Hz, 2H),12.30(d, J= 10.0 Hz, 1H) 2-196

(DMSO-d6-300)1.68(dd, J = 9.6, 5.8 Hz, 1H),1.96(dd, J = 8.9, 5.8 Hz,1H),3.09(t, J = 8.9 Hz, 1H), 7.24-7.34(m, 2H), 7.44-7.46(m, 1H),7.53(d,J = 8.7 Hz, 2H), 7.60(d,J = 4.1 Hz, 1H), 7.62(d, J = 3.8 Hz,1H),7.74-7.78(m, 4H), 8.07(brs,1H) 2-197

(DMSO-d6-300)1.62-1.68(m, 1H), 1.89-1.92(m,1H), 2.44(t, J = 4.5 Hz,4H),2.64(t, J = 5.8 Hz, 2H), 3.56(t,J = 4.5 Hz, 4H), 3.98(t, J = 5.8Hz,2H), 6.71-6.76(m, 3H), 7.09(t,J = 7.9 Hz, 1H), 7.52(d, J = 8.7Hz,2H), 7.55-7.58(m, 2H), 7.75(d,J = 8.7 Hz, 2H) 2-198

(DMSO-d6-300)1.63(dd, J = 9.8, 5.7 Hz, 1H)1.92(dd, J = 8.1, 5.5 Hz,1H),2.13(s, 3H), 2.34-2.43(m, 4H),2.56-2.66(m, 1H), 2.64(t,J = 5.7 Hz,2H), 3.97(t, J = 5.7 Hz,2H), 6.73-6.76(m, 3H), 7.11(t,J = 7.9 Hz, 1H),7.52-7.56(m, 4H),77.75(d, J = 8.7 Hz, 2H) 2-199

(DMSO-d6-300)1.77(dd, J = 9.8, 6.0 Hz, 1H),2.15(dd, J = 8.3, 6.0 Hz,1H),2.90(t, J = 8.7 Hz, 1H), 7.58(t,J = 8.3 Hz, 1H), 7.69(d, J = 8.3Hz,1H), 7.73(d, J = 4.1 Hz, 1H),7.87(d, J = 4.1 Hz, 1H), 8.05-8.09(m,2H), 8.18(d, J = 0.8 Hz,1H), 9.50(brs, 1H), 12.53(brs,1H) 2-200

(DMSO-d6-300)1.66(q, J = 4.8 Hz, 1H), 2.12(dd,J = 7.0, 5.5 Hz, 1H),2.79(s, 3H),2.70-3.44(m, 9H), 7.23-7.32(m,2H), 7.38(d, J = 4.1 Hz,2H),7.53(d, J = 8.7 Hz, 2H), 7.58(d,J = 4.9 Hz, 1H), 7.59(d, J = 4.9Hz,1H), 7.76(d, J = 8.3 Hz, 2H),9.23(s, 1H), 10.44(brs, 1H),12.33(brs,1H) 2-201

(DMSO-d6-300)1.55(dd, J = 9.0, 5.3 Hz, 1H),1.88(dd, J = 8.9, 5.1 Hz,1H),2.55(d, J = 5.1 Hz, 1H), 4.94(brs,2H), 6.33-6.44(m, 3H), 6.86(t,J =7.5 Hz, 1H), 7.69(d, J = 3.8 Hz,1H), 7.86(d, J = 4.1 Hz, 1H),8.18(s,1H), 9.26(brs, 1H),12.18(brs, 1H) 2-202

(MeOH-d4-400)2.07(dd, J = 6.0, 9.7 Hz, 1H),2.27(dd, J = 6.1, 7.9 Hz,1H), 2.74-2.78(m, 1H), 7.09(d, J = 8.5 Hz,2H), 7.37-7.49(m, 6H),7.66(d,J = 8.6 Hz, 2H) 2-203

(MeOH-d4-400)1.94(dd, J = 5.8, 9.8 Hz, 1H),2.12(dd, J = 5.9, 8.6 Hz,1H),2.79(t, J = 9.7 Hz, 1H), 7.18(d,J = 8.3 Hz, 2H), 7.36-7.44(m,5H),7.57(d, J = 4.0 Hz, 1H), 7.65(d,J = 8.6 Hz, 2H) 2-204

(DMSO-d6-300)1.71(dd, J = 9.8, 5.7 Hz, 1H),2.11(dd, J = 8.9, 5.5 Hz,1H),2.66(t, J = 8.5 Hz, 1H), 2.88(s,3H), 2.92(s, 3H), 3.74(d,J = 16.2Hz, 1H), 3.82(d, J = 17.0 Hz,1H), 6.94-6.99(m, 1H), 7.08-7.15(m, 3H),7.53(d, J = 8.7 Hz,2H), 7.57(t, J = 1.9 Hz, 1H),7.60(d, J = 3.8 Hz, 1H),7.76(d,J = 8.7 Hz, 2H), 9.30(brs, 1H),12.26(brs, 1H) 2-205

(DMSO-d6-300)1.70-1.75(m, 1H), 1.91-1.98(m,1H), 3.05-3.08(m, 1H),3.86(s,3H), 7.31-7.35(m, 2H), 7.45-7.48(m, 1H), 7.53(d, J = 8.7 Hz,2H),7.61(s, 2H), 7.72-7.77(m,3H), 8.40(brs, 1H), 12.28(brs,1H) 2-206

(DMSO-d6-300)1.68(dd, J = 5.1, 2.6 Hz, 1H),2.09(dd, J = 8.7, 5.3 Hz,1H),2.66(t, J = 9.2 Hz, 1H), 4.53(d,J = 14.7 Hz, 1H), 4.73(d, J = 14.7Hz,1H), 5.09(brs, 1H), 7.02-7.23(m,3H), 7.37(d, J = 7.2 Hz, 1H),7.53(d,J = 8.7 Hz, 2H), 7.57(d,J = 4.1 Hz, 1H), 7.59(d, J = 4.1 Hz,1H), 7.76(d,J = 8.3 Hz, 2H),9.28(brs, 1H), 12.16(brs, 1H) 2-207

(MeOH-d4-300)2.00(d, J = 6.0 Hz, 0.6H), 2.18-2.23(m, 0.4H), 2.20,2.23(2s,3H), 2.57(d, J = 6.0 Hz, 0.4H),2.58(d, J = 6.0 Hz, 0.6H),3.64(d,J = 12.0 Hz, 0.6H), 3.95(d,J = 12.0 Hz, 0.6H), 4.12(d,J = 12.0Hz, 0.4H), 4.33(d,J = 15.0 Hz, 0.6 H), 4.56(d,J = 15.0 Hz, 0.4H),4.67(d,J = 15.0 Hz, 0.4H), 4.91(d,J = 15.0 Hz, 0.6H), 7.10-7.24(m,4H),7.36-7.49(m, 3H), 7.56-7.70(m, 3H) 2-208

(CDCl3-300)2.09-2.11(m, 2H), 2.54(t,J = 7.5 Hz, 2H), 2.82-2.92(m,3H),3.60(s, 3H), 6.16(brs, 1H), 7.00-7.02(m, 3H), 7.12-7.17(m,2H),7.39(d, J = 8.3 Hz, 2H), 7.51(d,J = 8.3 Hz, 2H), 7.57(d, J = 3.8Hz,1H) 2-209

(DMSO-d6-400)1.60(dd, J = 10.2, 5.6 Hz, 1H),2.01(dd, J = 8.8, 5.6 Hz,1H),2.54(t, J = 8.3 Hz, 1H), 2.66-2.77(m, 3H), 3.26-3.64(m,9SH),7.00-7.09(m, 3H), 7.15(t,J = 7.4 Hz, 1H), 7.49-7.59(m,4H),7.73-7.77(m, 2H), 9.19(s, 1H) 2-210

(DMSO-d6-400)1.61(dd, J = 9.7, 5.6 Hz, 1H),2.01(dd, J = 8.8, 5.6 Hz,1H), 2.51-3.01(m, 13H), 3.26-3.36(m, 3H),7.02-7.09(m, 3H), 7.16(t,J =7.4 Hz, 1H), 7.50-7.59(m, 4H),7.73-7.79(m, 2H), 9.20(s, 1H),10.46(brs,1H), 12.21(brs, 1H) 2-211

(DMSO-d6-300)1.61(dd, J = 9.6, 5.5 Hz, 1H),2.02(dd, J = 8.7, 5.7 Hz,1H),2.55(t, J = 8.3 Hz, 1H), 2.67-2.79(m, 4H), 3.32-3.39(m,4H),3.59-3.74(m, 4H), 7.01-7.10(m,3H), 7.12-7.19(m, 1H), 7.50-7.60(m,4H), 7.73-7.78(m, 2H),9.20(s, 1H), 12.20(brs, 1H) 2-212

(DMSO-d6-300)1.63(dd, J = 9.4, 5.7 Hz, 1H),2.04(dd, J = 8.5, 5.8 Hz,1H),2.75(t, J = 9.0 Hz, 1H), 3.50(s,2H), 7.07-7.24(m, 4H), 7.70(d,J =3.8 Hz, 1H), 7.86(d, J = 3.8 Hz,1H), 8.18(d, J = 0.8 Hz, 1H),9.43(s,1H), 12.28(brs, 2H) 2-213

(DMSO-d6-300)1.53(dd, J = 9.4, 5.3 Hz, 1H),1.92(dd, J = 9.2, 5.5 Hz,1H),2.65(t, J = 9.2 Hz, 1H), 4.32(brs,2H), 4.45(s, 2H), 6.40-6.53(m,3H),6.96(t, J = 7.9 Hz, 1H),7.68(d, J = 3.8 Hz, 1H), 7.87(d,J = 3.8 Hz, 1H),7.89(dd, J = 8.1,5.8 Hz, 1H), 8.20(s, 1H), 8.46(d,J = 8.3 Hz, 1H),8.79(d, J = 5.3 Hz,1H), 8.84(d, J = 1.1 Hz, 1H),9.38(s, 1H), 11.92(brs,1H) 2-214

(DMSO-d6-400)1.55(dd, J = 10.0, 5.8 Hz, 1H),1.97(dd, J = 8.8, 5.6 Hz,1H),2.69(t, J = 9.3 Hz, 1H), 2.99(s,3H), 4.26(brs, 1H), 4.70(s,2H),6.56-6.60(m, 2H), 6.66(s, 1H),7.05(t, J = 8.1 Hz, 1H), 7.67(d,J =3.7 Hz, 1H), 7.86(d, J = 3.7 Hz,1H), 7.90(d, J = 7.4 Hz, 1H),8.18(d, J =0.9 Hz, 1H), 8.22(t,J = 3.2 Hz, 1H), 8.70(s, 1H),8.75(d, J = 5.1 Hz,1H), 9.37(s,1H), 12.17(brs, 1H) 2-215

(DMSO-d6-300)1.61-1.65(m, 1H), 1.79-1.83(m,1H), 2.66-2.70(m, 1H),2.73(s,3H), 3.00(s, 3H), 7.10-7.30(m,4H), 7.53(d, J = 8.7 Hz,2H),7.57(d, J = 3.8 Hz, 1H), 7.59(d,J = 3.8 Hz, 1H), 7.76(d, J = 9.0Hz,2H), 9.04(brs, 1H), 12.39(brs,1H) 2-216

(DMSO-d6-300)1.48-1.67(m, 1H), 1.73-1.81(m,1H), 2.04-2.44(m, 4H),2.65-2.68(m, 1H), 3.17-3.67(m, 7H),7.12(d, J = 7.2 Hz, 1H), 7.26-7.35(m,3H), 7.53(d, J = 8.7 Hz,2H), 7.58(s, 2H), 7.76(d,J = 8.7 Hz, 2H) 2-217

(MeOH-d4-300)1.52(s, 9H), 1.96(dd, J = 9.8,5.7 Hz, 1H), 2.11(dd, J =8.7,5.7 Hz, 1H), 2.74(t, J = 9.2 Hz, 1H),7.00-7.07(m, 1H),7.17-7.21(m,2H), 7.41-7.46(m, 4H), 7.63(d,J = 4.1 Hz, 1H), 7.68(d, J =8.7 Hz,2H) 2-218

(DMSO-d6-300)0.92(t, J = 5.7 Hz, 1H), 1.74(dd,J = 5.0, 2.5 Hz, 1H),2.89(dd,J = 9.6, 6.2 Hz, 1H), 6.84(d,J = 7.2 Hz, 1H), 6.95(dd, J =8.1,7.0 Hz, 1H), 7.12-7.17(m, 1H),7.36-7.40(m, 2H), 7.51-7.55(m,3H),7.70(d, J = 8.7 Hz, 2H),9.26(brs, 1H), 10.13(brs, 1H) 2-219

(DMSO-d6-300)1.64(dd, J = 5.3, 2.6 Hz, 1H), 1.97-2.06(m, 1H),2.68-2.77(m, 1H),3.60(s, 5H), 7.10(t, J = 7.3 Hz,3H), 7.20(t, J = 7.2Hz, 1H),7.70(d, J = 3.8 Hz, 1H), 7.86(d,J = 3.8 Hz, 1H), 8.17(s, 1H)2-220

(DMSO-d6-300)1.63(dd, J = 9.6, 5.5 Hz, 1H),2.02(dd, J = 8.7, 5.3 Hz,1H),2.76(t, J = 9.0 Hz, 1H), 3.35-3.54(m, 8H), 3.66(s, 2H), 7.07(t,J =7.9 Hz, 3H), 7.20(t, J = 7.7 Hz,1H), 7.70(d, J = 3.8 Hz, 1H),7.86(d, J =3.8 Hz, 1H), 8.18(d,J = 1.1 Hz, 1H), 9.42(brs, 1H),12.24(brs, 1H) 2-221

(DMSO-d6-300)1.63(dd, J = 10.0, 5.8 Hz, 1H),2.03(dd, J = 8.3, 5.7 Hz,1H),2.77(s, 3H), 2.80-3.04(m, 2H),3.23-3.52(m, 4H), 3.71(s,2H),2.98-4.19(m, 1H), 4.33-4.54(m,1H), 7.02-7.15(m, 3H), 7.22(t,J = 7.3Hz, 1H), 7.70(d, J = 4.1 Hz,1H), 7.86(d, J = 3.8 Hz, 1H),8.18(s, 1H),9.41(s, 1H),9.77(brs, 1H), 12.26(brs, 1H) 2-222

(DMSO-d6-300)1.01-1.31(m, 2H), 1.63(q,J = 4.9 Hz, 1H), 1.95-2.04(m,1H),2.71(t, J = 8.7 Hz, 1H), 2.89-3.01(m, 1H), 3.03-3.14(m,1H),3.54-3.70(m, 4H), 3.84-3.97(m,1H), 7.01-7.12(m, 3H), 7.18(t,J = 7.3Hz, 1H), 7.70(d, J = 3.8 Hz,1H), 7.86(d, J = 3.8 Hz, 1H),8.18(d, J = 0.8Hz, 1H) 2-223

(DMSO-d6-400)1.61(dd, J = 9.7, 5.6 Hz, 1H),1.94(dd, J = 8.3, 5.6 Hz,1H), 2.46-2.53(m, 2H), 2.70-2.83(m, 9H),6.93(d, J = 7.9 Hz, 1H),7.19(t,J = 8.1 Hz, 1H), 7.43-7.47(m, 2H),7.50-7.55(m, 2H), 7.57(s,2H),7.72-7.78(m, 2H), 9.23(s, 1H),10.17(s, 1H), 12.22(s, 1H) 2-224

(DMSO-d6-300)1.16-1.30(m, 2H), 1.59-1.71(m,3H), 1.99-2.01(m, 1H),2.51-2.54(m, 2H), 2.63-2.77(m, 3H),2.95-3.09(m, 2H), 3.60-3.67(m,2H),3.84-3.95(m, 1H), 7.02-7.14(m, 4H), 7.49-7.59(m, 4H),7.75(d, J = 8.3 Hz,2H), 8.32(brs,1H) 2-225

(MeOH-d4-400)1.89(dd, J = 5.7, 9.8 Hz, 1H),2.09(dd, J = 5.8, 8.5 Hz,1H),2.76(t, J = 9.2 Hz, 1H), 5.01(s,2H), 6.85-7.67(m, 15H) 2-226

(MeOH-d4-400)1.82(dd, J = 5.9, 9.8 Hz, 1H),2.05(dd, J = 5.8, 8.7 Hz,1H),2.77(t, J = 9.3 Hz, 1H), 4.50(s,2H), 7.16-7.65(m, 7H) 2-227

(DMSO-d6-300)1.18-1.24(m, 3H), 1.44(d,J = 4.9 Hz, 1H), 1.55-1.57(m,1H),1.84-1.87(m, 1H), 1.98-2.01(m,1H), 3.24(t, J = 6.2 Hz, 2H),7.11-7.24(m, 5H), 7.50-7.56(m, 4H),7.74(d, J = 8.7 Hz, 2H) 2-228

(DMSO-d6-300)1.58(q, J = 5.1 Hz, 1H), 1.99(dd,J = 8.3, 5.7 Hz, 1H),2.71(t,J = 9.8 Hz, 1H), 2.85(s, 6H), 6.49-6.62(m, 3H), 7.04(t, J = 7.7Hz,1H), 7.69(d, J = 4.1 Hz, 1H),7.86(d, J = 3.8 Hz, 1H), 8.18(s,1H),9.38(s, 1H), 12.19(brs, 1H) 2-229

(MeOH-d4-300)1.84(d, J = 4.5 Hz, 1H), 2.07(d,J = 5.3 Hz, 1H), 3.76(d, J= 11.3 Hz,1H), 3.87(d, J = 11.3 Hz, 1H), 7.11-7.29(m, 5H), 7.38(d, J =3.0 Hz,1H), 7.42(d, J = 9.0 Hz, 2H),7.58(d, J = 3.0 Hz, 1H), 7.65(d,J =9.0 Hz, 2H) 2-230

(DMSO-d6-300)1.65(dd, J = 9.4, 5.7 Hz, 1H),2.12(dd, J = 8.9, 5.8 Hz,1H), 2.49-2.58(m, 2H), 2.72-3.06(m, 3H),3.43-3.54(m, 4H),7.00-7.16(m,5H), 7.71(d, J = 3.8 Hz, 1H),7.88(d, J = 4.1 Hz, 1H),8.19(s,1H), 9.49(brs, 1H), 12.27(brs,1H) 2-231

(DMSO-d6-300)1.64(dd, J = 9.2, 5.5 Hz, 1H),2.11(dd, J = 13.8, 4.7 Hz,1H),2.53-2.56(m, 1H), 2.74-2.88(m,2H), 2.84(s, 3H), 2.93(s,3H),2.94-3.00(m, 2H), 7.01-7.16(m,4H), 7.71(d, J = 3.8 Hz, 1H),7.88(d, J= 3.8 Hz, 1H), 8.19(s,1H), 9.51(brs, 1H), 12.25(brs,1H) 2-232

(DMSO-d6-300)1.65-1.70(m, 1H), 2.14-2.16(m,1H), 2.59-2.61(m, 1H),2.84-2.92(m, 7H), 3.27-3.53(m, 4H),3.99-4.10(m, 2H), 4.43-4.55(m,2H),7.05-7.16(m, 4H), 7.72(d,J = 3.8 Hz, 1H), 7.89(d, J = 4.1 Hz,1H),8.20(s, 1H), 9.52(brs, 1H),12.30(brs, 1H) 2-233

(DMSO-d6-300)1.16(t, J = 9.6 Hz, 2H), 1.35(t,J = 11.5 Hz, 1H),1.45-1.88(m, 5H),1.92-2.06(m, 2H), 2.59-2.75(m,1H), 3.17-3.65(m, 3H),4.85-4.99(m, 1H), 7.00-7.19(m, 4H),7.69(d, J = 3.8 Hz, 1H), 7.85(d,J =3.8 Hz, 1H), 8.17(s, 1H),12.26(brs, 1H) 2-234

(DMSO-d6-300)1.62(dd, J = 9.8, 5.7 Hz, 1H),2.04(dd, J = 8.5, 5.8 Hz,1H), 2.54-2.59(m, 2H), 2.69-2.79(m, 3H),3.34-3.61(m, 8H),7.04-7.09(m,3H), 7.13-7.20(m, 1H), 7.70(d,J = 4.1 Hz, 1H), 7.86(d, J =3.8 Hz,1H), 8.18(s, 1H), 9.40(brs, 1H),12.24(brs, 1H) 2-235

(DMSO-d6-300)1.63(dd, J = 9.4, 5.7 Hz, 1H),2.04(dd, J = 8.7, 5.7 Hz,1H), 2.62-2.65(m, 2H), 2.71-2.97(m, 10H),3.28-3.37(m, 2H),3.99-4.07(m,1H), 4.41-4.48(m, 1H), 7.05-7.09(m, 3H), 7.16-7.19(m,1H),7.70(d, J = 4.1 Hz, 1H), 7.87(d,J = 4.1 Hz, 1H), 8.19(s,1H),9.42(brs, 1H), 10.51(brs, 1H),12.23(brs, 1H) 2-236

(DMSO-d6-300)1.59-1.71(m, 3H), 2.03(dd, J = 8.5,5.5 Hz, 1H),2.49-2.57(m, 2H),2.74(t, J = 9.0 Hz, 1H), 3.39(t,J = 6.4 Hz, 2H),4.43(brs, 1H),6.99-7.07(m, 3H), 7.15(t,J = 7.5 Hz, 1H), 7.69(d, J = 4.1Hz,1H), 7.86(d, J = 4.1 Hz, 1H),8.18(d, J = 0.8 Hz, 1H), 9.39(brs,1H),12.22(brs, 1H) 2-237

(DMSO-d6-400)1.24(d, J = 7.0 Hz, 3H), 1.96(dq,J = 10.7, 7.0 Hz, 1H),2.75(d,J = 10.7 Hz, 1H), 7.13-7.27(m, 5H),7.49-7.58(m, 4H),7.71-7.76(m,2H) 2-238

(DMSO-d6-300)1.63(q, J = 5.3 Hz, 1H), 1.85(t,J = 7.2 Hz, 2H), 2.04(dd, J= 8.7,5.7 Hz, 1H), 2.60(t, J = 7.5 Hz, 1H),2.77(t, J = 6.6 Hz, 4H),2.90-3.36(m, 7H), 4.02(t, J = 6.6 Hz, 4H),7.02-7.09(m, 3H), 7.18(t,J =7.3 Hz, 1H), 7.70(d, J = 3.8 Hz,1H), 7.87(d, J = 4.1 Hz, 1H),8.19(d, J =0.8 Hz, 1H), 9.41(s,1H), 10.53(brs, 1H), 12.24(brs, 1H) 2-239

(CDCl3-300)1.25-1.29(m, 2H), 1.75-1.99(m,2H), 2.12(dd, J = 8.7, 6.0 Hz,1H),2.25(dd, J = 9.2, 6.6 Hz, 1H), 2.60(q, J = 4.6 Hz, 1H), 2.72(dd, J=13.0, 7.3 Hz, 1H), 2.88(t, J =9.2 Hz, 1H), 3.29-3.32(m, 4H),3.57(t, J =4.9 Hz, 4H), 3.67-3.70(m, 1H), 6.15(brs, 1H), 6.91(s,1H), 6.95(s, 1H),7.01(d, J = 7.5Hz, 1H), 7.10(d, J = 7.5 Hz, 1H),7.21(t, J = 7.5 Hz, 1H),7.45(d, J =3.8 Hz, 1H), 7.66(d, J = 3.8 Hz, 1H) 2-240

(DMSO-d6-300)1.65-1.76(m, 1H), 2.04-2.16(m,1H), 2.62-2.82(m, 2H),2.90-3.05(m, 1H), 3.53-3.67(m, 2H),4.52(t, J = 5.8 Hz, 1H), 6.96-7.22(m,4H), 7.72(d, J = 3.0 Hz,1H), 7.87(d, J = 3.8 Hz, 1H),8.19(s, 1H),9.41(brs, 1H),12.20(brs, 1H) 2-241

(MeOH-d4-300)1.94(dd, J = 9.8, 5.7 Hz, 1H), 2.12-2.14(m, 4H), 2.78(t, J= 9.0 Hz,1H), 7.09(d, J = 4.1 Hz, 1H), 7.16-7.28(m, 5H), 7.48(d, J = 4.1Hz,1H), 7.52(s, 1H), 8.00(s, 1H) 2-242

(DMSO-d6-300)1.64-1.74(m, 1H), 2.05-2.17(m,1H), 2.65-2.79(m, 1H),2.80-2.94(m, 1H), 3.06-3.19(m, 1H),3.26-3.38(m, 4H), 3.46-3.58(m,4H),4.16-4.28(m, 2H), 7.04-7.18(m, 4H), 7.71(d, J = 3.8 Hz,1H), 7.87(d, J =3.8 Hz, 1H),8.19(s, 1H), 9.46(brs, 1H),12.26(brs, 1H) 2-243

(DMSO-d6-300)1.73(dd, J = 9.8, 5.7 Hz, 1H),2.13(dd, J = 7.9, 5.7 Hz,1H),2.69(t, J = 9.2 Hz, 1H), 3.23-3.62(m, 8H), 3.81(dd, J = 21.7,16.4Hz, 2H), 6.95-7.03(m, 1H),7.05-7.21(m, 3H), 7.71(d,J = 4.1 Hz, 1H),7.88(d, J = 3.8 Hz,1H), 8.19(s, 1H), 9.51(brs, 1H),12.32(brs, 1H) 2-244

(MeOH-d4-400)1.85-1.90(m, 1H), 2.11(dd, J = 5.7,8.6 Hz, 1H),2.81-2.85(m, 1H),3.64(brs, 2H), 7.14-7.27(m, 6H),7.44(dd, J = 2.2, 9.0Hz, 1H), 7.91-8.07(m, 4H) 2-245

(MeOH-d4-400)1.88(dd, J = 6.1, 10.2 Hz, 1H),2.08(dd, J = 5.7, 8.6 Hz,1H),2.74(t, J = 9.2 Hz, 1H), 3.05-3.07(m, 4H), 3.77-3.80(m, 4H),6.83(d,J = 8.7 Hz, 2H), 7.14(d,J = 8.6 Hz, 2H), 7.37-7.48(m, 3H),7.57(d, J =4.0 Hz, 1H), 7.65(d,J = 8.6 Hz, 2H) 2-246

(MeOH-d4-400)1.89(dd, J = 5.7, 9.8 Hz, 1H),2.08(dd, J = 5.8, 8.6 Hz,1H),2.77(t, J = 9.2 Hz, 1H), 2.91-3.04(m, 5H), 3.20-3.31(m,2H),3.56-3.58(m, 2H), 3.77-3.84(m,2H), 6.90(d, J = 8.6 Hz, 2H),7.20(d, J= 8.4 Hz, 2H), 7.39-7.45(m, 3H), 7.57(d, J = 4.0 Hz,1H), 7.66(d, J = 8.6Hz, 2H) 2-247

(MeOH-d4-400)2.05(dd, J = 5.9, 9.7 Hz, 1H), 2.26-2.30(m, 1H),2.69-2.73(m, 1H),2.88-3.05(m, 5H), 3.18-3.36(m,2H), 3.52-3.65(m, 2H),3.74-3.87(m, 2H), 6.93(d, J = 8.6 Hz,2H), 7.12(d, J = 8.6 Hz, 2H),7.39-7.50(m, 4H), 7.67(d, J = 8.6 Hz, 2H) 2-248

(MeOH-d4-300)1.04(t, J = 7.2 Hz, 1H), 1.31-1.47(m, 2H), 1.75-1.85(m,2H),1.98-2.01(m, 1H), 2.22(d,J = 6.0 Hz, 1H), 3.46(t, J = 6.6 Hz,2H),7.13-7.32(m, 5H), 7.63-7.68(m, 3H) 2-249

(MeOH-d4-300)1.44-1.47(m, 2H), 1.85-1.94(m,3H), 2.09(d, J = 5.7 Hz, 1H),2.39-2.49(m, 6H), 3.68(t, J = 4.7 Hz,4H), 7.14-7.21(m, 5H), 7.38(d,J =4.1 Hz, 1H), 7.44(d, J = 8.7 Hz,2H), 7.59(d, J = 4.1 Hz, 1H),7.67(d, J =8.7 Hz, 2H) 2-250

(DMSO-d6-300)1.61(dd, J = 9.8, 5.7 Hz, 1H),1.97(dd, J = 8.7, 5.7 Hz,1H),2.73(t, J = 9.0 Hz, 1H), 3.40(t,J = 4.5 Hz, 4H), 3.60(t, J = 4.3Hz,4H), 6.81(d, J = 7.9 Hz, 1H),7.11(t, J = 7.9 Hz, 1H), 7.30(d,J = 7.9Hz, 1H), 7.38(s, 1H),7.71(d, J = 4.1 Hz, 1H), 7.86(d,J = 4.1 Hz, 1H),8.18(d, J = 0.8 Hz,1H), 8.50(s, 1H), 9.43(s, 1H),12.23(brs, 1H) 2-251

(DMSO-d6-300)1.60(q, J = 5.0 Hz, 1H), 1.95(t,J = 7.2 Hz, 1H), 2.70(t, J= 9.0 Hz,1H), 3.40(t, J = 4.7 Hz, 4H),3.59(t, J = 4.7 Hz, 4H), 6.81(d,J= 7.5 Hz, 1H), 7.10(t, J = 7.9 Hz,1H), 7.29(d, J = 9.0 Hz, 1H),7.37(s,1H), 7.53(d, J = 8.7 Hz,2H), 7.57(s, 2H), 7.76(d,J = 8.7 Hz, 2H),8.50(s, 1H),9.22(s, 1H), 12.19(brs, 1H) 2-252

(DMSO-d6-300)1.65-1.76(m, 3H), 2.10-2.12(m,1H), 2.54-2.81(m, 3H),3.49(t,J = 6.4 Hz, 2H), 7.04-7.12(m, 4H),7.71(d, J = 3.8 Hz, 1H),7.87(d,J = 4.1 Hz, 1H), 8.18(s, 1H) 2-253

(DMSO-d6-300)1.70-1.74(m, 1H), 1.84-1.89(m.2H), 2.08-2.14(m, 1H),2.60-2.68(m, 2H), 2.76-2.90(m, 1H),3.31-3.38(m, 4H), 3.49-3.57(m,4H),4.06-4.10(m, 2H), 7.06-7.16(m, 4H), 7.71(d, J = 4.1 Hz,1H), 7.88(d, J =3.8 Hz, 1H),8.19(s, 1H), 9.48(brs, 1H),12.21(brs, 1H) 2-254

(DMSO-d6-300)1.68-1.91(m, 7H), 2.08-2.15(m,1H), 2.62-2.69(m, 1H),2.76-2.90(m, 2H), 3.26-3.32(m, 2H),3.47-3.51(m, 1H), 3.70-3.74(m,1H),4.02-4.07(m, 2H), 4.70-4.72(m, 1H), 7.04-7.15(m, 4H),7.71(d, J = 4.1 Hz,1H), 7.87(d,J = 4.1 Hz, 1H), 8.18(s, 1H),9.50(brs, 1H), 12.20(brs, 1H)2-255

(DMSO-d6-300)1.70-1.92(m, 5H), 2.08-2.15(m,1H), 2.61-2.72(m, 2H),2.80-2.83(m, 1H), 3.16-3.21(m, 1H),3.31-3.39(m, 3H), 4.04-4.07(m,1H),4.22-4.25(m, 1H), 4.91-4.92(m, 1H), 7.05-7.15(m, 4H),7.71(d, J = 3.8 Hz,1H), 7.87(d,J = 4.1 Hz, 1H), 8.19(s, 1H),9.51(brs, 1H), 12.20(brs, 1H)2-256

(MeOH-d4-300)1.00(d, J = 6.8 Hz, 3H), 1.25-1.85(m, 6H), 2.04(dd, J =9.0,5.7 Hz, 1H), 2.66(t, J = 9.0 Hz, 1H),2.90(t, J = 11.8 Hz, 2H),3.60(d,J = 11.8 Hz, 2H), 6.05(d, J = 4.1 Hz,1H), 7.13-7.33(m, 6H) 2-257

(DMSO-d6-300)1.60(dd, J = 9.8, 5.5 Hz, 1H),2.03(dd, J = 8.7, 5.5 Hz,1H),2.74(dd, J = 9.8, 8.7 Hz, 1H), 3.03-3.12(m, 4H), 3.70-3.78(m,4H),6.72(d, J = 7.2 Hz, 1H), 6.79-6.88(m, 2H), 7.12(t, J = 7.9 Hz,1H),7.69(d, J = 4.1 Hz, 1H),7.87(d, J = 4.1 Hz, 1H), 8.18(s,1H), 9.38(brs,1H) 2-258

(DMSO-d6-300)1.67(dd, J = 9.7, 5.7 Hz, 1H),2.11(dd, J = 8.7, 5.7 Hz,1H),2.84(dd, J = 9.7, 8.7 Hz, 1H), 3.17-3.711(m, 8H), 7.20-7.26(m,2H),7.31-7.40(m, 2H), 7.71(d,J = 4.1 Hz, 1H), 7.87(d, J = 4.1 Hz,1H),8.18(s, 1H), 9.41(brs, 1H),12.32(brs, 1H) 2-259

(DMSO-d6-300)1.63(dd, J = 10.0, 5.8 Hz, 1H),2.04(dd, J = 8.3, 5.8 Hz,1H),2.65(t, J = 7.9 Hz, 2H), 2.75(dd,J = 10.0, 8.3 Hz, 1H),3.13-3.27(m,2H), 3.23(t, J = 4.7 Hz, 4H),3.52(t, J = 4.7 Hz, 4H),6.58-6.64(m, 1H), 6.99-7.09(m, 2H),7.114-7.22(m, 1H), 7.70(d,J = 4.1 Hz,1H), 7.86(d, J = 4.1 Hz,1H), 8.18(s, 1H), 9.42(s, 1H),12.24(s, 1H) 2-260

(DMSO-d6-300)1.64(q, J = 4.9 Hz, 1H), 1.98(dd,J = 8.9, 5.1 Hz, 1H),2.81(t,J = 9.6 Hz, 1H), 3.18-4.24(m, 11H),7.00(d, J = 7.2 Hz, 1H),7.25(t,J = 8.3 Hz, 1H), 7.47-7.51(m, 2H),7.72(d, J = 4.1 Hz, 1H),7.87(d,J = 3.8 Hz, 1H), 8.19(s, 1H),9.45(s, 1H), 10.56(brs,1H),12.28(brs, 1H) 2-261

(DMSO-d6-300)1.63(dd, J = 10.0, 5.8 Hz, 1H),1.97(dd, J = 8.5, 6.2 Hz,1H),2.77(t, J = 9.4 Hz, 1H), 3.18-4.23(m, 10H), 7.00(d, J = 7.2 Hz,1H),7.24(t, J = 8.1 Hz, 1H), 7.46-7.59(m, 6H), 7.76(d, J = 8.7 Hz,2H),9.25(s, 1H), 10.70(brs, 1H),12.24(brs, 1H) 2-262

(DMSO-d6-300)1.25(d, J = 6.8 Hz, 3H), 1.97(dd,J = 10.2, 6.4 Hz, 1H),2.76(d,J = 10.2 Hz, 1H), 7.12-7.29(m, 5H),7.52(d, J = 8.7 Hz, 2H),7.56(s,2H), 7.74(d, J = 8.7 Hz, 2H) 2-263

(MeOH-d4-300)1.85(d, J = 6.0 Hz, 1H), 1.94-2.04(m, 1H), 2.13-2.21(m,1H),2.20(d, J = 5.7 Hz, 1H), 3.42(t,J = 7.0 Hz, 2H), 7.18-7.23(m,5H),7.40(d, J = 4.1 Hz, 1H), 7.45(d,J = 8.7 Hz, 2H), 7.58(d, J = 3.8Hz,1H), 7.67(d, J = 8.7 Hz, 2H) 2-264

(CDCl3-300)11.26(s, 1H), 1.50(s, 2H), 1.83-1.85(m, 1H), 2.02(s, 3H),2.21-2.23(m, 1H), 3.97-3.99(m, 2H),6.09(s, 1H), 6.99(s, 1H),7.08-7.09(m, 2H), 7.23-7.25(m, 3H),7.44(d, J = 4.0 Hz, 1H), 7.63(d,J =4.0 Hz, 1H) 2-265

(MeOH-d4-400)1.95(dd, J = 5.8, 9.8 Hz, 1H),2.14(dd, J = 5.8, 8.6 Hz,1H),2.87(t, J = 9.2 Hz, 1H), 4.05(s,2H), 7.32-7.40(m, 5H), 7.44(d,J =8.6 Hz, 2H), 7.58(d, J = 4.0 Hz,1H), 7.66(d, J = 8.6 Hz, 2H) 2-266

(MeOH-d4-400)1.97(dd, J = 5.8, 9.8 Hz, 1H),2.19(dd, J = 5.9, 8.6 Hz,1H), 2.88-2.93(m, 1H), 2.95(s, 3H), 3.07(s,3H), 7.31(d, J = 8.3 Hz, 2H),7.37(d,J = 8.1 Hz, 2H), 7.65-7.68(m, 3H) 2-267

(DMSO-d6-300)1.64(q, J = 5.0 Hz, 1H), 1.92(dd,J = 8.1, 5.8 Hz, 1H),2.67(t,J = 7.9 Hz, 1H), 3.03(t, J = 4.3 Hz,4H), 3.50(t, J = 4.5 Hz,4H),6.91(d, J = 7.9 Hz, 1H), 7.00(d,J = 8.7 Hz, 1H), 7.12-7.19(m,2H),7.70(d, J = 3.8 Hz, 1H), 7.85(d,J = 4.1 Hz, 1H), 8.17(s,1H),9.87(brs, 1H), 12.27(brs, 1H) 2-268

(DMSO-d6-300)1.63(q, J = 5.1 Hz, 1H), 2.02(dd,J = 8.7, 6.8 Hz, 1H),2.65(t,J = 7.2 Hz, 1H), 2.72(t, J = 6.8 Hz,1H), 3.54(t, J = 7.3 Hz,1H),4.62(brs, 1H), 7.00-7.08(m, 3H),7.15(t, J = 7.3 Hz, 1H), 7.69(d,J =3.8 Hz, 1H), 7.86(d, J = 3.8 Hz,1H), 8.17(s, 1H), 9.38(brs,1H),12.24(brs, 1H) 2-269

(DMSO-d6-300)1.63(q, J = 5.1 Hz, 1H), 1.91(dd,J = 7.7, 6.2 Hz, 1H),2.66(t,J = 8.9 Hz, 1H), 3.03(t, J = 4.1 Hz,4H), 3.50(t, J = 4.5 Hz,4H),6.91(d, J = 7.9 Hz, 1H), 7.00(d,J = 7.9 Hz, 1H), 7.12-7.19(m,2H),7.52(d, J = 8.7 Hz, 2H), 7.57(s,2H), 7.76(d, J = 8.7 Hz,2H),9.91(brs, 1H), 12.28(brs, 1H) 2-270

(DMSO-d6-300)1.63(dd, J = 9.6, 5.5 Hz, 1H),2.05(dd, J = 8.9, 5.5 Hz,1H),2.75(t, J = 9.0 Hz, 1H), 2.79(t,J = 7.3 Hz, 1H), 4.05(t, J = 7.2Hz,2H), 6.45(brs, 2H), 7.06-7.12(m,3H), 7.17(d, J = 6.8 Hz, 1H),7.69(d,J = 4.1 Hz, 1H), 7.86(d,J = 4.1 Hz, 1H), 8.18(d, J = 0.8 Hz,1H),9.41(brs, 1H), 12.12(brs,1H) 2-271

(MeOH-d4-400)1.95(dd, J = 5.5, 9.6 Hz, 1H),2.14(dd, J = 6.0, 8.0 Hz,1H),2.78(t, J = 9.1 Hz, 1H), 2.94-3.72(complexm, 10H), 7.28-7.38(m,4H),7.65-7.70(m, 3H) 2-272

(MeOH-d4-300)1.30-1.38(m, 3H), 1.81(d,J = 6.0 Hz, 1H), 1.88(s, 3H),1.93-2.03(m, 1H), 2.19(d, J = 6.0 Hz,1H), 3.06-3.08(m, 2H), 7.16-7.23(m,5H), 7.40(d, J = 4.1 Hz,1H), 7.45(dd, J = 6.6, 2.1 Hz, 2H),7.57(d, J =4.1 Hz, 1H), 7.67(dd,J = 6.6, 2.1 Hz, 2H) 2-273

(MeOH-d4-300)1.71-1.73(m, 4H), 2.19(d,J = 6.0 Hz, 1H), 4.03-4.05(m,2H),6.21(t, J = 2.3 Hz, 1H), 7.16-7.23(m, 5H), 7.41-7.46(m, 4H),7.53(d,J = 4.1 Hz, 1H), 7.67(dd,J = 6.6, 2.1 Hz, 2H) 2-274

(DMSO-d6-300)1.16(s, 3H), 1.34(s, 3H), 2.56(s,1H), 7.13-7.29(m, 5H),7.51(d,J = 8.7 Hz, 2H), 7.55(s, 2H),7.73(d, J = 8.7 Hz, 2H),9.03(brs,1H), 12.28(brs, 1H) 2-275

(DMSO-d6-300)1.17(s, 3H), 1.34(s, 3H), 2.57(s,1H), 7.13-7.31(m, 5H),7.69(d,J = 4.1 Hz, 1H), 7.84(d, J = 4.1 Hz,1H), 8.15(s, 1H), 9.23(brs,1H),12.31(brs, 1H) 2-276

(DMSO-d6-300)1.64(dd, J = 9.7, 5.7 Hz, 1H), 1.97-2.12(m, 3H),2.43-2.49(m, 2H),2.70-2.84(m, 1H), 3.71-3.85(m,2H), 6.98(d, J = 7.5 Hz,1H),7.24(dd, J = 7.9, 7.5 Hz, 1H),7.50(d, J = 7.9 Hz, 1H), 7.53(s,1H),7.71(d, J = 4.1 Hz, 1H),7.86(d, J = 4.1 Hz, 1H), 8.18(s,1H), 9.41(brs,1H), 12.26(brs,1H) 2-277

(MeOH-d4-400)2.68(t, J = 7.0 Hz, 1H), 3.03(d,J = 7.0 Hz, 1H), 3.18(dd, J= 7.0,17.5 Hz, 1H), 3.50(d, J = 17.3 Hz,1H), 7.06(s, 3H),7.24-7.28(m,1H), 7.65-7.67(m, 3H) 2-278

(DMSO-d6-400)1.60(dd, J = 5.5, 9.6 Hz, 1H),2.02(dd, J = 5.8, 8.2 Hz,1H),2.31(t, J = 7.7 Hz, 2H), 2.70-2.75(m, 3H), 6.74(s, 1H), 7.11(q,J =8.1 Hz, 4H), 7.26(s, 1H),7.69(d, J = 3.9 Hz, 1H), 7.86(d,J = 3.9 Hz,1H), 8.17(s, 1H),9.39(s, 1H) 2-279

(DMSO-d6-400)1.60(dd, J = 5.6, 9.7 Hz, 1H),2.02(dd, J = 5.7, 8.4 Hz,1H), 2.55-2.59(m, 2H), 2.70-2.77(m, 3H),3.37-3.43(m, 4H),3.48-3.53(m,4H), 7.13(s, 4H), 7.69(d,J = 3.9 Hz, 1H), 7.86(d, J = 3.9Hz,1H), 8.17(s, 1H), 9.39(s, 1H) 2-280

(DMSO-d6-400)1.61(dd, J = 5.6, 9.8 Hz, 1H),2.02(dd, J = 5.7, 8.4 Hz,1H), 2.59-3.60(complexm, 16H), 7.14(s, 4H),7.87(d, J = 3.9 Hz, 1H),8.18(s,1H), 9.39(s, 1H) 2-281

(DMSO-d6-400)1.60(dd, J = 5.6, 9.7 Hz, 1H),2.02(dd, J = 5.8, 8.4 Hz,1H), 2.29-2.33(m, 2H), 2.54(d, J = 4.5 Hz,3H), 2.70-2.76(m, 3H),7.10(dd,J = 8.0, 19.3 Hz, 4H), 7.69(d,J = 3.9 Hz, 1H), 7.71-7.73(m,1H),7.86(d, J = 3.9 Hz, 1H), 8.17(s,1H), 9.38(s, 1H) 2-282

(DMSO-d6-400)1.60(dd, J = 5.6, 9.8 Hz, 1H),2.02(dd, J = 5.7, 8.5 Hz,1H), 2.52-2.56(m, 2H), 2.69-2.75(m, 3H),2.80(s, 3H), 2.90(s, 3H),7.12(s,4H), 7.69(d, J = 3.9 Hz, 1H),7.86(d, J = 3.9 Hz, 1H), 8.18(s,1H),9.39(s, 1H) 2-283

(DMSO-d6-300)1.66(dd, J = 9.8, 5.7 Hz, 1H),2.07(dd, J = 8.7, 5.7 Hz,1H),2.80(dd, J = 9.8, 8.7 Hz, 1H),5.38(s, 2H), 7.23-7.36(m, 4H),7.70(d,J = 3.8 Hz, 1H), 7.86(d,J = 3.8 Hz, 1H), 8.18(s, 1H),9.43(s, 1H),12.31(s, 1H) 2-284

(DMSO-d6-400)0.42-0.58(m, 10H), 0.98(d,J = 5.6 Hz, 1H), 1.07-1.21(m,1H),1.35(d, J = 5.6 Hz, 1H), 2.12-2.14(m, 2H), 6.33-6.40(m, 5H),6.57(d,J = 4.2 Hz, 1H), 6.62(d,J = 8.8 Hz, 2H), 6.75(d, J = 4.2 Hz,1H), 6.85(d,J = 8.8 Hz, 2H) 2-285

(MeOH-d4-300)1.54-1.57(m, 2H), 1.85-1.86(m,1H), 1.92(d, J = 6.0 Hz, 1H),2.01-2.04(m, 1H), 2.24(d, J = 6.0 Hz,1H), 2.77-2.88(m, 2H), 7.19-7.24(m,5H), 7.39(d, J = 4.1 Hz,1H), 7.43(dd, J = 6.8, 1.9 Hz, 2H)7.56(d, J =4.1 Hz, 1H), 7.65(dd,J = 6.8, 1.9Hz, 2H) 2-286

(MeOH-d4-300)1.33(d, J = 6.8 Hz, 3H), 2.14(dd,J = 10.5, 6.8 Hz, 1H),2.84(d,J = 10.5 Hz, 1H), 4.01(s, 2H), 7.16-7.23(m, 5H), 7.57(dd, J =8.3,1.9 Hz, 1H), 7.79(brs, 1H),7.83(d, J = 7.9 Hz, 1H), 7.93-7.97(m,2H), 8.08(brs, 1H) 2-287

(MeOH-d4-400)1.37(d, J = 6.5 Hz, 3H), 2.14(s,3H), 2.16-2.24(m, 1H),2.94(d,J = 10.2 Hz, 1H), 7.08(d, J = 4.2 Hz,1H), 7.16-7.30(m, 5H),7.48(dd,J = 4.2, 0.9 Hz, 1H), 7.51(s, 1H),7.99(brs, 1H) 2-288

(DMSO-d6-300)1.27(d, J = 6.4 Hz, 3H), 2.01(dd,J = 10.4, 7.0 Hz, 1H),2.80(d,J = 10.2 Hz, 1H), 7.11-7.34(m, 5H),7.70(d, J = 3.8 Hz, 1H),7.85(d,J = 3.8 Hz, 1H), 8.17(s, 1H),9.28(brs, 1H), 12.35(brs, 1H) 2-289

(MeOH-d4-400)1.95(dd, J = 5.8, 9.8 Hz, 1H),2.15(dd, J = 5.8, 8.6 Hz,1H),2.91(t, J = 9.2 Hz, 1H), 4.05(s,2H), 7.36(dt, J = 8.2, 8.2 Hz,4H),7.65-7.68(m, 3H) 2-290

(DMSO-d6-400)1.61(dd, J = 5.6, 9.6 Hz, 1H),2.03(dd, J = 5.8, 8.2 Hz,1H),2.74(t, J = 9.2 Hz, 1H), 2.81(s,3H), 2.96(s, 3H), 3.4-3.8(s,2H),7.10(d, J = 8.0 Hz, 2H), 7.15(d,J = 8.0 Hz, 2H), 7.69(d, J = 3.8Hz,1H), 7.86(d, J = 3.8 Hz, 1H),8.17(s, 1H), 9.40(s, 1H) 2-291

(DMSO-d6-400)1.59(dd, J = 5.5, 9.4 Hz, 1H),2.00(dd, J = 5.9, 7.9 Hz,1H),2.71(t, J = 9.1 Hz, 1H), 3.41-3.48(m, 8H), 3.62(s, 2H), 7.07(d,J =7.8 Hz, 2H), 7.13(d, J = 7.8 Hz,2H), 7.66(d, J = 3.7 Hz, 1H),7.82(d, J =3.7 Hz, 1H), 8.12(s,1H), 9.36(s, 1H) 2-292

(MeOH-d4-400)1.93(dd, J = 5.8, 9.8 Hz, 1H),2.14(dd, J = 5.9, 8.5 Hz,1H),2.83(t, J = 9.2 Hz, 1H), 3.44(s,2H), 7.18-7.24(m, 4H), 7.65-7.68(m,3H) 2-293

(DMSO-d6-400)1.61(dd, J = 5.5, 9.3 Hz, 1H), 2.02-2.05(m, 1H), 2.56(s,3H), 2.74(t,J = 9.1 Hz, 1H), 3.33(s, 2H),7.15(m, 4H), 7.70(d, J = 3.6Hz,1H), 7.86(d, J = 3.6 Hz, 1H),7.94(s, 1H), 8.17(s, 1H), 9.40(s,1H)2-294

(MeOH-d4-400)1.91(dd, J = 5.8, 9.7 Hz, 1H),2.13(dd, J = 5.9, 8.4 Hz,1H), 2.47-4.33(complexm, 14H), 7.16(d,J = 8.0 Hz, 2H), 7.27(d, J = 7.9Hz,2H), 7.65-7.69(m, 3H), 8.89(s,2H) 2-295

(DMSO-d6-300)1.58(d, J = 5.7 Hz, 1H), 1.77-1.87(m, 1H), 2.03-2.20(m,2H),3.56-3.70(m, 2H), 6.38(brs, 2H),7.11-7.26(m, 5H), 7.47-7.56(m,4H),7.73(d, J = 8.7 Hz, 2H),9.19(brs, 1H), 12.19(brs, 1H) 2-296

(DMSO-d6-300)1.23(d, J = 6.8 Hz, 3H), 1.80(dd,J = 10.4, 6.6 Hz, 1H),2.61(d,J = 10.5 Hz, 1H), 6.85(brs, 1H),7.04(brs, 1H), 7.12-7.28(m,5H),7.74(d, J = 3.8 Hz, 1H), 7.87(d,J = 3.8 Hz, 1H), 8.17(s,1H),9.11(brs, 1H) 2-297

(DMSO-d6-300)1.21(d, J = 6.8 Hz, 3H), 1.77(dd,J = 10.7, 6.6 Hz, 1H),2.39(d,J = 4.1 Hz, 3H), 2.58(d, J = 10.5 Hz,1H), 7.09-7.27(m, 5H),7.49(d,J = 4.9 Hz, 1H), 7.72(d, J = 3.8 Hz,1H), 7.87(d, J = 3.8 Hz,1H),8.16(s, 1H), 9.01(brs, 1H) 2-298

(MeOH-d4-300)1.61-1.76(m, 10H), 2.17(d,J = 5.7 Hz, 1H), 2.96-2.99(m,1H),4.95-4.98(m, 1H), 7.19(t,J = 7.9 Hz, 5H), 7.38(d, J = 4.1 Hz,1H),7.43(d, J = 8.7 Hz, 2H),7.55(d, J = 4.1 Hz, 1H), 7.66(d,J = 8.7 Hz, 2H)2-299

(MeOH-d4-400)1.07(t, J = 7.3 Hz, 3H), 1.70-1.80(m, 1H), 1.82-1.93(m,1H),2.03-2.10(m, 1H), 2.98(d,J = 10.5 Hz, 1H), 7.15-7.28(m,5H),7.64-7.68(m, 3H) 2-300

(MeOH-d4-400)1.93(dd, J = 6.0, 9.9 Hz, 1H),2.12(dd, J = 5.8, 8.5 Hz,1H),2.88(dd, J = 8.0, 15.0 Hz, 1H),3.13(t, J = 7.8 Hz, 2H), 3.18-3.24(m,2H), 7.17(d, J = 7.9 Hz,2H), 7.28(d, J = 7.9 Hz, 2H), 7.65-7.68(m, 3H)2-301

(MeOH-d4-400)1.91(dd, J = 5.8, 9.7 Hz, 1H),2.13(dd, J = 6.1, 8.4 Hz,1H),2.75(t, J = 7.0 Hz, 2H), 2.81(t,J = 9.2 Hz, 1H), 3.69(t, J = 7.0Hz,2H), 7.10(d, J = 7.9 Hz, 2H),7.19(d, J = 7.8 Hz, 2H), 7.64-7.67(m,3H) 2-302

(MeOH-d4-400)1.73-1.81(m, 2H), 1.91(dd, J = 5.3,9.4 Hz, 1H),2.11-2.15(m, 1H),2.61(t, J = 7.6 Hz, 2H), 2.80(t,J = 8.9 Hz, 1H),3.52(t, J = 6.4 Hz,2H), 7.08(d, J = 7.7 Hz, 2H),7.17(d, J = 7.8 Hz, 2H),7.65-7.67(m, 3H) 2-303

(DMSO-d6-300)1.48(d, J = 6.0 Hz, 1H), 1.83(q,J = 7.4 Hz, 1H), 2.11(d, J= 5.3 Hz,1H), 2.16-2.25(m, 1H), 2.65(s,6H), 3.62(q, J = 8.3 Hz,1H),3.81(q, J = 5.4 Hz, 1H), 7.11-7.19(m, 3H), 7.23(d, J = 7.2 Hz,1H),7.27(d, J = 4.1 Hz, 1H), 7.48-7.57(m, 4H), 7.74(d, J = 8.3 Hz,2H),9.23(s, 1H), 12.19(brs, 1H) 2-304

(DMSO-d6-300)1.26(d, J = 6.0 Hz, 6H), 1.68(dd,J = 8.7, 5.8 Hz, 1H),2.13(dd,J = 8.5, 5.8 Hz, 1H), 2.83(dd,J = 8.7, 8.5 Hz, 1H),3.14-3.98(m,3H), 7.27-7.49(m, 4H), 7.72(d,J = 3.8 Hz, 1H), 7.88(d, J =3.8 Hz,1H), 8.19(s, 1H), 9.45(s, 1H) 2-305

(DMSO-d6-400)1.41-1.91(m, 5H), 2.43-2.53(m,1H), 2.76(d, J = 9.7 Hz,1H),2.99(td, J = 13.0, 7.4 Hz, 1H),7.04-7.18(m, 4H), 7.70(d,J = 3.7 Hz,1H), 7.85(d, J = 3.7 Hz,1H), 8.17(s, 1H), 9.26(brs, 1H),12.43(brs, 1H)2-306

(DMSO-d6-300)1.80(d, J = 6.0 Hz, 1H), 2.13(d,J = 5.7 Hz, 1H),3.20-3.44(m, 8H),4.21(d, J = 11.3 Hz, 1H), 4.26(d,J = 11.3 Hz, 1H),7.15-7.29(m, 5H),7.70(d, J = 3.8 Hz, 1H), 7.86(d,J = 4.1 Hz, 1H),8.18(s, 1H),9.52(brs, 1H), 12.43(brs, 1H) 2-307

(DMSO-d6-300)1.63(dd, J = 10.2, 6.0 Hz, 1H),2.06(dd, J = 8.7, 5.7 Hz,1H),2.79(t, J = 9.4 Hz, 1H), 7.15-7.31(m, 5H), 7.62-7.73(m, 4H),7.89(d,J = 8.7 Hz, 2H), 9.49(brs,1H), 12.27(brs, 1H) 2-308

(DMSO-d6-300)1.02(s, 3H), 1.04(s, 3H), 1.75(d,J = 5.7 Hz, 1H), 2.14(d, J= 5.3 Hz,1H), 2.93-3.00(m, 2H), 3.20-3.29(m, 2H), 3.43-3.50(m,1H),4.15(d, J = 11.7 Hz, 1H), 4.26(d,J = 10.9 Hz, 1H), 6.92(t, J = 5.7Hz,1H), 7.16-7.25(m, 5H), 7.70(d,J = 3.8 Hz, 1H), 7.86(d, J = 4.1Hz,1H), 8.17(s, 1H), 9.38(brs, 1H),12.40(brs, 1H) 2-309

(DMSO-d6-300)1.68-1.79(m, 5H), 2.11-2.16(m,1H), 2.87-2.92(m, 2H),3.54-3.72(m, 3H), 4.15(d, J = 11.3 Hz,1H), 4.25(d, J = 12.8 Hz, 1H),6.96-7.01(m, 1H), 7.17-7.25(m, 5H),7.70(d, J = 3.8 Hz, 1H), 7.86(d,J =3.8 Hz, 1H), 8.17(s, 1H),9.35(brs, 1H), 12.40(brs, 1H) 2-310

(DMSO-d6-300)1.21-1.37(m, 4H), 1.39-1.51(m,2H), 1.77(d, J = 6.0 Hz,1H),2.15(d, J = 6.0 Hz, 1H), 3.13-3.24(m, 4H), 4.16(d, J = 12.0 Hz,1H),4.25(d, J = 12.0 Hz, 1H), 7.11-7.32(m, 5H), 7.70(d, J = 3.0 Hz,1H),7.87(d, J = 3.0 Hz, 1H),8.18(s, 1H), 9.49(s, 1H),12.40(brs, 1H) 2-311

(acetone-d6-400)2.14-2.19(m, 5H), 2.89(t,J = 9.2 Hz, 1H), 6.06(s, 1H),7.73-7.74(m, 1H), 7.81-7.82(m, 2H) 2-312

(CD3CN-400)2.95(dd, J = 5.0, 9.0 Hz, 1H),3.21(d, J = 9.0 Hz, 1JH),4.03(d,J = 10.3 Hz, 1H), 4.46(dd, 5.0,10.3 Hz, 1H), 7.28-7.41(m,5H),7.47(s, 1H), 7.65(d, J = 3.9 Hz,1H), 7.75(d, J = 3.9 Hz, 1H) 2-313

(acetone-d6-400)2.05(m, 1H), 2.11-2.15(m, 1H),2.33(s, 3H), 2.77-2.82(m,1H),6.00(s, 1H), 7.74-7.82(m, 3H) 2-314

(acetone-d6-400)2.16(dd, J = 5.8, 9.7 Hz, 1H), 2.27-2.31(m, 1H), 2.37(s,3H),2.80(dd, J = 7.9, 9.6 Hz, 1H),5.97(s, 1H), 7.68-7.83(m, 3H) 2-315

(acetone-d6-400)2.05-2.07(m, 1H), 2.12-2.15(m,1H), 2.81(t, J = 9.3 Hz,1H),2.88(t, J = 6.4 Hz, 2H), 3.79(t,J = 6.2 Hz, 2H), 6.09(s, 1H),7.74-7.81(m, 3H) 2-316

(acetone-d6-400)2.17(dd, J = 5.7, 9.6 Hz, 1H), 2.25-2.31(m, 1H), 2.82(t,J = 8.8 Hz,1H), 2.92(t, J = 6.4 Hz, 2H),3.82(t, J = 6.5 Hz, 2H),6.05(s,1H), 7.68-7.82(m, 3H) 2-317

(acetone-d6-400)2.08-2.09(m, 1H), 2.15-2.18(m,1H), 2.84(t, J = 9.7 Hz,1H),4.62(s, 2H), 6.20(s, 1H), 7.74-7.82(m, 3H) 2-318

(acetone-d6-400)2.18-2.22(m, 1H), 2.33(t,J = 6.7 Hz, 1H), 2.85(t, J =8.7 Hz,1H), 4.67(s, 2H), 6.19(s, 1H),7.69-7.82(m, 3H) 2-319

(CDCl3-300)0.87(d, J = 7.2 Hz, 3H), 0.94(d,J = 6.4 Hz, 3H), 1.26-1.29(m,1H),1.89-1.93(m, 2H), 2.13(d,J = 6.4 Hz, 1H), 2.22-2.24(m, 1H),2.43(d, J= 5.7 Hz, 1H), 2.65-2.73(m, 1H), 3.44-3.49(m, 1H),5.93(brs, 1H),7.18-7.26(m, 5H),7.37(d, J = 7.9 Hz, 2H), 7.53-7.56(m, 3H), 7.76(d, J =3.8 Hz, 1H) 2-320

(DMSO-d6-300)1.77(d, J = 6.0 Hz, 1H), 2.14(d,J = 6.0 Hz, 1H), 2.67(s,3H),2.70(s, 3H), 4.13(d, J = 12.0 Hz,1H), 4.23(d, J = 12.0 Hz, 1H),7.16-7.28(m, 5H), 7.70(d, J = 3.0 Hz,1H), 7.87(d, J = 3.0 Hz,1H),8.18(s, 1H), 9.47(s, 1H),12.40(brs, 1H) 2-321

(DMSO-d6-300)0.91(t, J = 7.5 Hz, 3H), 1.75(d,J = 6.0 Hz, 1H), 2.16(d, J= 6.0 Hz,1H), 2.81-2.96(m, 2H), 4.13(d,J = 12.0 Hz, 1H), 4.28(d, J =12.0 Hz,1H), 6.89-6.97(m, 1H), 7.13-7.28(m, 5H), 7.70(d, J = 3.0 Hz,1H),7.87(d, J = 3.0 Hz, 1H),8.18(s, 1H), 9.38(s, 1H),12.37(brs, 1H) 2-322

(DMSO-d6-300)2.10-2.23(m, 1H), 2.90-4.11(m,1oH), 7.14-7.47(m, 5H),7.69(d,J = 4.1 Hz, 1H), 7.86(d, J = 4.1 Hz,1H), 8.19(s, 1H), 9.53(brs,1H),9.75(brs, 1H), 12.49(brs, 1H) 2-323

(DMSO-d6-300)1.20(d, J = 6.4 Hz, 2H), 1.73(dt,J = 10.5, 6.5 Hz, 1H),2.56(d,J = 10.5 Hz, 1H), 7.11-7.27(m, 5H),7.74(d, J = 3.8 Hz, 1H),7.86(d,J = 3.8 Hz, 1H), 8.15(s, 1H),8.62(brs, 1H), 8.92(brs,1H),10.21(brs, 1H) 2-324

(DMSO-d6-300)1.21(d, J = 6.8 Hz, 3H), 1.82(dd,J = 10.4, 6.6 Hz, 1H),2.62(d,J = 9.8 Hz, 1H), 5.21(s, 2H), 7.12-7.30(m, 7H), 7.49(dd, J =8.5,1.7 Hz, 1H), 7.63(d, J = 8.3 Hz, 1H),7.69-7.78(m, 3H), 8.60(brs,1H),12.18(brs, 1H) 2-325

(DMSO-d6-300)1.14(d, J = 6.4 Hz, 3H), 1.53(dd,J = 10.9, 6.4 Hz, 1H),2.38(d,J = 10.5 Hz, 1H), 5.21(s, 2H), 7.07-7.25(m, 7H), 7.48(d, J = 8.3Hz,1H), 7.62(d, J = 8.3 Hz, 1H),7.70(s, 1H), 7.78(d, J = 8.3 Hz,2H),8.36(brs, 1H), 8.60(brs,1H), 10.13(brs, 1H) 2-326

(CDCl3-300)1.25(d, J = 5.3 Hz, 3H), 2.18-2.29(m, 1H), 2.77-2.89(m,1H),7.11-7.34(m, 6H), 7.37(d,J = 8.3 Hz, 2H), 7.48(d, J = 8.3 Hz,2H),7.60(d, J = 3.0 Hz, 1H) 2-327

(MeOH-d4-400)1.07(t, J = 7.3 Hz, 3H), 1.68-1.80(m, 1H), 1.83-1.93(m,1H),2.07(ddd, J = 5.8, 9.9, 10.1 Hz,1H), 2.99(d, J = 10.5 Hz, 1H),7.15-7.27(m, 5H), 7.65-7.68(m, 3H) 2-328

(MeOH-d4-400)1.07(t, J = 7.3 Hz, 3H), 1.68-1.80(m, 1H), 1.82-1.93(m,1H),2.07(ddd, J = 5.8, 9.9, 10.1 Hz,1H), 2.99(d, J = 10.5 Hz, 1H),7.15-7.27(m, 5H), 7.64-7.68(m, 3H) 2-329

(DMSO-d6-300)1.62-1.94(m, 4H), 2.12(d,J = 6.8 Hz, 1H), 2.41(d, J = 6.8Hz,1H), 2.53-2.68(m, 2H), 2.92-3.16(m, 2H), 3.42-3.57(m,1H),3.81-3.95(m, 1H), 7.21-7.43(m,5H), 7.71(d, J = 4.1 Hz, 1H),7.87(d, J= 4.1 Hz, 1H), 8.20(s,1H), 9.53(brs, 1H), 9.76(brs,1H), 12.50(brs, 1H)2-330

(DMSO-d6-300)1.14-1.35(m, 1H), 1.47-1.76(m,5H), 2.12(d, J = 6.8 Hz, 1H),2.70-2.97(m, 2H), 3.07-3.44(m, 3H),3.77-3.91(m, 1H), 7.16-7.46(m,5H),7.70(d, J = 3.8 Hz, 1H),7.87(d, J = 3.8 Hz, 1H), 8.20(s,1H), 9.16(brs,1H), 9.52(brs,1H), 12.50(brs, 1H) 2-331

(DMSO-d6-300)0.25-0.30(m, 1H), 0.44-0.49(m,1H), 1.75-1.81(m, 1H),2.09-2.14(m, 1H), 2.29-2.36(m, 1H),4.12(d, J = 11.3 Hz, 1H), 4.29(d,J =10.2 Hz, 1H), 7.12-7.23(m, 6H),7.69(d, J = 3.8 Hz, 1H), 7.86(d,J = 3.8Hz, 1H), 8.17(s, 1H),12.43(brs, 1H) 2-332

(DMSO-d6-300)1.79(d, J = 5.7 Hz, 1H), 2.11(d,J = 4.5 Hz, 1H),2.68-2.79(m, 2H),3.06-3.17(m, 2H), 3.36(s, 3H),4.13(d, J = 8.7 Hz, 1H),4.22(d,J = 11.3 Hz, 1H), 7.18-7.25(m, 5H),7.69(d, J = 4.1 Hz, 1H),7.86(d,J = 3.8 Hz, 1H), 8.17(s, 1H),12.43 (brs, 1H) 2-333

(DMSO-d6-300)1.77(d, J = 5.7 Hz, 1H), 2.13(d,J = 4.9 Hz, 1H), 2.93(dd, J= 6.3,3.1 Hz, 2H), 3.30(t, J = 6.0 Hz, 2H),4.15(d, J = 11.3 Hz, 1H),4.24(d,J = 10.5 Hz, 1H), 6.87(t, J = 5.5 Hz,1H), 7.16-7.24(m, 5H),7.69(d,J = 4.1 Hz, 1H), 7.85(d, J = 3.8 Hz,1H), 8.117(s, 1H), 12.41(brs,0H) 2-334

(DMSO-d6-300)1.04(d, J = 6.0 Hz, 1H), 1.78(d,J = 5.7 Hz, 1H),2.07-2.17(m, 4H),2.12(s, 3H), 3.17-3.22(m, 4H),4.19(d, J = 10.9 Hz, 1H),4.25(d,J = 11.7 Hz, 1H), 7.13-7.28(m, 5H),7.70(d, J = 3.8 Hz, 1H),7.86(d,J = 3.8 Hz, 1H), 8.18(s, 1H) 2-335

(DMSO-d6-300)1.76(d, J = 6.0 Hz, 1H), 2.13(d,J = 5.3 Hz, 1H), 4.11(d, J= 11.3 Hz,1H), 4.25(d, J = 11.7 Hz, 1H),6.36(brs, 2H), 7.12-7.28(m,5H),7.69(d, J = 3.8 Hz, 1H), 7.85(d,J = 4.1 Hz, 1H), 8.17(s,1H),12.41(brs, 1H) 2-336

(DMSO-d6-300)2.08-2.13(m, 1H), 2.73-2.76(m,1H), 3.23-3.33(m, 2H),3.28(s,3H), 3.35(s, 3H), 3.51-3.61(m,2H), 3.76-3.85(m, 1H), 4.14-4.18(m,1H), 7.33-7.37(m, 5H),7.70(d, J = 3.8 Hz, 1H), 7.88(d,J = 3.8 Hz, 1H),8.21(s, 1H),9.50(brs, 1H), 12.51(brs, 1H) 2-337

(MeOH-d4-300)2.12(d, J = 6..0 Hz, 1H), 2.30(d,J = 6.0 Hz, 1H),2.61-2.63(m, 2H),2.80(brs, 6H), 3.13-3.15(m, 3H),3.59-3.75(m, 3H),7.31-7.40(m,8H), 7.57-7.67(m, 3H) 2-338

(DMSO-d6-300)1.28(d, J = 6.8 Hz, 3H), 2.02(dd,J = 10.2, 6.8 Hz, 1H),2.81(d,J = 10.2 Hz, 1H), 7.19-7.30(m, 5H),7.71(d, J = 3.8 Hz, 1H),7.81(s,1H), 7.85(d, J = 3.8 Hz, 1H) 2-339

(MeOH-d4-400)1.50(s, 3H), 1.75(d, J = 5.8 Hz,1H), 2.19(d, J = 5.8 Hz,1H),6.93(t, J = 8.8 Hz, 2H), 7.23(dd,J = 5.4, 8.7 Hz, 2H),7.62-7.66(m,3H) 2-340

(MeOH-d4-400)1.44(s, 3H), 1.82(d, J = 6.1 Hz,1H), 2.16(d, J = 6.2 Hz,1H),7.00(t, J = 8.8 Hz, 2H), 7.21-7.25(m, 2H), 7.44(d, J = 3.9 Hz,1H),7.62-7.64(m, 2H) 2-341

(DMSO-d6-300)2.15(d, J = 6.4 Hz, 1H), 2.42-2.49(m, 1H), 2.90-3.13(m,3H),3.24-3.27(m, 2H), 3.60-3.97(m,5H), 7.21-7.42(m, 5H), 7.53(d,J = 8.7Hz, 2H), 7.57(d, J = 4.1 Hz,1H), 7.58(d, J = 4.1 Hz, 1H),7.75(d, J = 8.7Hz, 2H), 9.32(brs,1H), 10.17(brs, 1H), 12.48(brs,1H) 2-342

(DMSO-d6-300)1.73-1.93(m, 1H), 2.61-2.94(m,6H), 3.24-3.37(m, 4H),3.82-4.01(m, 4H), 7.17-7.29(m, 5H),7.70(d, J = 4.1 Hz, 1H), 7.88(d,J =3.8 Hz, 1H), 8.21(s, 1H),9.42(brs, 1H) 2-343

(MeOH-d4-300)1.14-1.34(m, 6H), 2.37(d,J = 7.2 Hz, 1H), 2.66(d, J = 6.0Hz,1H), 3.18-3.30(m, 4H), 3.52(d,J = 13.9 Hz, 1H), 3.99(d, J = 14.3Hz,1H), 7.34-7.45(m, 5H), 7.70-7.71(m, 3H) 2-344

(MeOH-d4-300)1.09(d, J = 6.0 Hz, 3H), 1.15-1.25(m, 3H), 2.40(d, J = 6.0Hz,1H), 2.59-2.80(m, 3H), 3.13(d,J = 12.0 Hz, 1H), 3.50(d, J = 15.0Hz,1H), 3.57(d, J = 12.0 Hz, 1H), 3.69-3.83(m, 2H), 4.02(d, J = 12.0Hz,1H), 7.27-7.47(m, 8H), 7.548(d,J = 3.0 Hz, 1H), 7.65(d, J = 9.0Hz,2H) 2-345

(MeOH-d4-300)1.93(d, J = 6.0 Hz, 1H), 2.23(d,J = 6.0 Hz, 1H), 2.30(dd, J= 6.0,12.0 Hz, 1H), 2.39(dd, J = 6.0,12.0 Hz, 1H), 2.99(d, J = 12.0Hz,1H), 3.11(d, J = 12.0 Hz, 1H),3.46(t, J = 6.0 Hz, 2H), 7.12-7.29(m,5H), 7.38(d, J = 3.0 Hz,1H), 7.43(d, J = 9.0 Hz, 2H),7.57(d, J = 3.0 Hz,1H), 7.66(d,J = 9.0 Hz, 2H) 2-346

(DMSO-d6-300)2.21-2.31(m, 2H), 4.36(d,J = 14.3 Hz, 1H), 4.77(d, J = 14.3Hz,1H), 6.98-7.06(m, 2H), 7.15-7.23(m, 3H), 7.48-7.56(m, 4H),7.60(s,2H), 7.76(d, J = 9.0 Hz,2H), 8.78(s, 1H), 9.46(brs, 1H),12.56(brs, 1H)2-347

(MeOH-d4-300)1.99(d, J = 6.0 Hz, 1H), 2.20(d,J = 6.0 Hz, 1H),3.41-3.42(m, 2H),3.60-3.62(m, 2H), 3.74-3.79(m,2H), 7.17-7.33(m, 5H),7.40(d,J = 4.1 Hz, 1H), 7.45(d, J = 8.7 Hz,2H), 7.59(d, J = 4.1 Hz,1H),7.67(d, J = 8.7 Hz, 2H) 2-348

(MeOH-d4-300)1.03(d, J = 6.8 Hz, 3H), 1.15(d,J = 6.8 Hz, 3H), 2.36(d, J= 7.2 Hz,1H), 2.48-2.57(m, 2H), 3.40(d,J = 14.7 Hz, 1H), 3.91(d, J =14.7 Hz,1H), 7.23-7.30(m, 3H), 7.35-7.46(m, 5H), 7.60(d, J = 3.8 Hz,1H),7.67(d, J = 8.7 Hz, 2H) 2-349

(MeOH-d4-300)1.06-1.07(m, 6H), 1.90(d,J = 6.0 Hz, 1H), 2.25(d, J = 6.0Hz,1H), 2.53-2.55(m, 1H), 2.94(d,J = 12.8 Hz, 1H), 3.12(d, J = 12.8Hz,1H), 7.18-7.27(m, 5H), 7.41(d,J = 4.1 Hz, 1H), 7.45(d, J = 8.7Hz,2H), 7.59(d, J = 4.1 Hz, 1H),7.67(d, J = 8.7 Hz, 2H) 2-350

(CDCl3-300)1.98-2.11(m, 1H), 2.20-2.34(m,1H), 2.47-2.58(m, 2H),2.68-2.86(m, 1H), 2.98(d, J = 9.8 Hz,1H), 5.81(s, 1H), 7.01-7.16(m,3H),7.19(d, J = 3.8 Hz, 1H), 7.29-7.35(m, 1H), 7.39(d, J = 8.7 Hz,2H),7.50(d, J = 8.7 Hz, 2H),7.61(d, J = 3.8 Hz, 1H) 2-351

(CDCl3-300)1.87-2.33(m, 2H), 2.44-2.58(m,2H), 2.69-2.85(m, 1H), 2.96(d,J= 9.8 Hz, 1H), 5.90(s, 1H),6.98(s, 1H), 7.01-7.07(m, 1H),7.09-7.19(m,2H), 7.28-7.34(m,1H), 7.44(d, J = 3.8 Hz, 1H),7.65(d, J = 3.8 Hz, 1H)2-352

(MeOH-d4-300)1.21(t, J = 7.5 Hz, 3H), 1.91(d,J = 6.0 Hz, 1H), 2.14(d, J= 6.0 Hz,1H), 2.86(d, J = 15.0 Hz, 1H),2.96(d, J = 15.0 Hz, 1H),3.08(d,J = 12.0 Hz, 1H), 3.17(d, J = 12.0 Hz,1H), 4.07(q, J = 7.0 Hz,2H), 7.10-7.28(m, 5H), 7.36(d, J = 3.0 Hz,1H), 7.42(d, J = 9.0 Hz,2H),7.58(d, J = 3.0 Hz, 1H), 7.66(d,J = 9.0 Hz, 2H) 2-353

(MeOH-d4-300)1.38(d, J = 6.8 Hz, 3H), 2.21(dd,J = 10.5, 6.8 Hz, 1H),2.94(d,J = 10.5 Hz, 1H), 6.90-7.36(m, 7H),7.64-7.65(m, 2H) 2-354

(MeOH-d4-300)1.39(d, J = 6.8 Hz, 3H), 2.22(dd,J = 10.5, 6.8 Hz, 1H),2.94(d,J = 10.5 Hz, 1H), 6.93-7.15(m, 7H),7.67-7.68(m, 2H) 2-355

(DMSO-d6-300)1.85-2.06(m, 4H), 2.25-2.64(m,2H), 5.23(s, 2H),6.95-7.14(m,4H), 7.22(d, J = 8.7 Hz, 2H),7.49(dd, J = 8.3, 2.3 Hz,1H),7.64(d, J = 8.3 Hz, 1H), 7.71(d,J = 2.3 Hz, 1H), 7.76(d, J = 8.7Hz,2H), 8.54(s, 1H), 12.02(brs, 1H) 2-356

(CDCl3-300)1.87(d, J = 6.0 Hz, 1H), 2.10(d,J = 6.0 Hz, 1H), 3.56(d, J =9.8 Hz,1H), 3.74(d, J = 9.8 Hz, 1H),4.35(d, J = 12.1 Hz, 1H), 4.46(d,J =12.1 Hz, 1H), 6.10(s, 1H), 7.13-7.35(m, 11H), 7.37-7.43(m, 3H),7.50(d, J= 8.7 Hz, 2H) 2-357

(MeOH-d4-300)1.93(d, J = 6.0 Hz, 1H), 2.24(d,J = 6.0 Hz, 1H), 2.82(s,3H),2.88(s, 3H), 3.03-3.10(m, 3H),3.19(d, J = 12.0 Hz, 1H), 7.14-7.27(m,5H), 7.38(d, J = 3.0 Hz,1H), 7.43(d, J = 9.0 Hz, 2H),7.57(d, J = 3.0 Hz,1H), 7.65(d,J = 9.0 Hz, 2H) 2-358

(MeOH-d4-300)1.89(d, J = 6.0 Hz, 1H), 2.20(d,J = 6.0 Hz, 1H), 2.89(d, J= 15.0 Hz,1H), 2.99(d, J = 15.0 Hz, 1H),3.07(d, J = 12.0 Hz, 1H),3.20(d,J = 12.0 Hz, 1H), 7.11-7.30(m, 5H),7.38(d, J = 3.0 Hz, 1H),7.42(d,J = 9.0 Hz, 2H), 7.57(d, J = 3.0 Hz,1H), 7.65(d, J = 9.0 Hz, 2H)2-359

(MeOH-d4-300)1.73(d, J = 6.0 Hz, 1H), 2.15(d,J = 6.0 Hz, 1H),2.98-3.14(m, 4H),3.35-3.58(m, 8H), 7.12-7.29(m,5H), 7.40(d, J = 3.0 Hz,1H),7.44(d, J = 9.0 Hz, 2H), 7.60(d,J = 3.0 Hz, 1H), 7.68(d, J = 9.0Hz,2H) 2-360

(DMSO-d6-300)1.64-1.79(m, 2H), 1.95-2.15(m,2H), 2.24-2.59(m, 2H),5.26(s,2H), 6.90-7.07(m, 4H), 7.24(d,J = 9.0 Hz, 2H), 7.48(dd, J =8.3,2.3 Hz, 1H), 7.65(d, J = 8.3 Hz, 1H),7.72(d, J = 2.3 Hz, 1H),7.81(d,J = 9.0 Hz, 2H), 8.23(brs, 1H),8.64(brs, 1H), 9.75(brs, 1H) 2-361

(DMSO-d6-300)1.82(d, J = 6.4 Hz, 1H), 2.17(d,J = 6.0 Hz, 1H), 3.01(d, J= 13.6 Hz,1H), 7.26-7.32(m, 6H), 7.53(d,J = 8.7 Hz, 2H), 7.60(d, J = 4.1Hz,3H), 7.76(d, J = 8.3 Hz, 2H) 2-362

(CDCl3-300)1.75(d, J = 6.4 Hz, 1H), 2.17(d,J = 6.8 Hz, 1H), 2.57-2.68(m,1H),3.14-3.17(m, 1H), 3.34(d,J = 14.7 Hz, 1H), 3.78(d, J = 15.1 Hz,1H),4.02(dd, J = 8.3, 4.1 Hz, 1H),4.14(dd, J = 15.6, 8.9 Hz,1H),7.18-7.29(m, 6H), 7.39(d,J = 8.7 Hz, 2H), 7.53(d, J = 8.3 Hz,2H),7.59(d, J = 3.8 Hz, 1H),7.97(brs, 1H) 2-363

(DMSO-d6-400)1.44-1.76(m, 5H), 2.37-2.58(m,2H), 2.88-2.92(m, 1H),5.20(s,2H), 6.94-7.10(m, 4H), 7.17(d,J = 8.8 Hz, 2H), 7.47(dd, J =8.3,2.3 Hz, 1H), 7.62(d, J = 8.3 Hz, 1H),7.69(d, J = 2.3 Hz, 1H),7.75(d,J = 8.8 Hz, 2H) 2-364

(DMSO-d6-300)1.69-1.92(m, 2H), 2.08-2.59(m,4H), 6.91-6.98(m, 1H),7.00-7.12(m, 3H), 7.54(d, J = 8.7 Hz,2H), 7.62-7.67(m, 2H), 7.78(d,J =8.7 Hz, 2H), 8.70(brs, 1H),9.78(brs, 1H) 2-365

(DMSO-d6-300)1.47-1.69(m, 3H), 1.71-1.90(m,2H), 2.43-2.51(m, 1H),2.74(d,J = 9.9 Hz, 1H), 2.95-3.02(m, 1H),7.02-7.21(m, 4H), 7.59(d,J =4.0 Hz, 1H), 7.84(d, J = 4.0 Hz,1H), 8.03(dd, J = 8.1, 1.0 Hz,1H),8.08(d, J = 8.1 Hz, 1H), 8.63(d,J = 1.0 Hz, 1H), 12.38(brs, 1H)2-366

(DMSO-d6-300)1.25(d, J = 6.6 Hz, 3H), 1.98(dq,J = 10.6, 6.6 Hz, 1H),2.77(d,J = 10.6 Hz, 1H), 7.14-7.30(m, 5H),7.57(d, J = 4.0 Hz, 1H),7.82(d,J = 4.0 Hz, 1H), 8.01-8.08(m, 1H),8.07(d, J = 9.2 Hz, 1H),8.62(d,J = 1.5 Hz, 1H), 9.05(s, 1H),12.26(s, 1H) 2-367

(MeOH-d4-300)1.36(d, J = 6.6 Hz, 3H), 2.12-2.25(m, 4H), 2.86(d, J = 10.6Hz,1H), 7.17-7.21(m, 7H), 7.53(d,J = 4.0 Hz, 1H), 7.98(d, J = 1.5 Hz,1H)2-368

(MeOH-d4-300)2.02(d, J = 6.6 Hz, 1H), 2.22(d,J = 5.9 Hz, 1H), 3.80(dd, J= 14.3,4.4 Hz, 1H), 3.94(d, J = 13.9 Hz,1H), 7.14-7.24(m, 5H), 7.39(d,J= 4.0 Hz, 1H), 7.43(d, J = 8.4 Hz,2H), 7.50-7.66(m, 1H), 7.60(d,J = 4.0Hz, 1H), 7.66(d, J = 8.4 Hz,2H), 7.95-8.03(m, 2H), 8.56-8.60(m, 1H)2-369

(DMSO-d6-300)1.95-2.30(m, 3H), 2.78(d,J = 9.9 Hz, 1H), 3.99-4.18(m,2H),6.81(d, J = 7.7 Hz, 1H), 6.96(t,J = 6.8 Hz, 1H), 7.11(t, J = 6.8Hz,1H), 7.28(d, J = 7.0 Hz, 1H),7.52(d, J = 8.8 Hz, 2H), 7.57(s,2H),7.75(d, J = 8.4 Hz, 2H),9.08(brs, 1H), 12.42(brs, 1H) 2-370

(DMSO-d6-300)1.95-2.29(m, 3H), 2.80(d,J = 9.5 Hz, 1H), 4.01-4.18(m,2H),6.81(dd, J = 7.9, 1.3 Hz, 1H),6.97(td, J = 7.4, 1.2 Hz, 1H),7.12(td,J = 7.8, 1.6 Hz, 1H),7.28(d, J = 7.3 Hz, 1H), 7.70(d,J = 3.7 Hz, 1H),7.86(d, J = 4.0 Hz,1H), 8.16(s, 1H), 9.30(brs, 1H),12.45(brs, 1H) 2-371

(DMSO-d6-300)1.63(dd, J = 10.0, 5.5 Hz, 1H),2.05(dd, J = 10.4, 2.9 Hz,1H),2.84(t, J = 9.2 Hz, 1H), 7.14-7.27(m, 5H), 7.31(d, J = 3.8 Hz,1H),7.43(d, J = 3.8 Hz, 1H),7.97(s, 1H), 9.53(s, 1H),12.20(s, 1H) 2-372

(DMSO-d6-300)1.26(d, J = 6.8 Hz, 1H), 2.01(dt,J = 17.0, 6.8 Hz, 1H),2.88(d,J = 17.0 Hz, 1H), 7.15-7.29(m, 5H),7.31(d, J = 4.1 Hz, 1H),7.43(d,J = 3.8 Hz, 1H), 7.95(s, 1H),9.39(s, 1H), 12.23(s, 1H) 2-373

(DMSO-d6-300)1.43-1.96(m, 6H), 2.84(d,J = 9.8 Hz, 1H), 2.94-3.10(m,1H),7.03-7.22(m, 5H), 7.32(d,J = 3.8 Hz, iH), 7.44 (d, J = 3.8 Hz,1H),7.97(s, 1H), 9.40(s, 1H),12.38(s, 1H) 2-374

(CDCl3-300)1.32(d, J = 7.0 Hz, 3H), 2.27-2.39(m, 1H), 2.48(s, 3H),3.05(d,J = 10.3 Hz, 1H), 6.26(s, 1H), 7.11-7.28(m, 6H), 7.32(d, J = 4.0Hz,1H), 7.59(d, J = 4.0 Hz, 1H) 2-375

(CDCl3-300)1.41-1.94(m, 4H), 2.09-2.29(m,1H), 2.33-2.72(m, 4H),2.89-3.14(m, 2H), 6.27(s, 1H), 6.94-7.69(m, 7H) 2-376

(DMSO-d6-400)1.55(d, J = 5.6 Hz, 1H), 1.69(s,3H), 1.97(d, J = 5.6 Hz,1H),3.20(dd, J = 13.7, 4.4 Hz, 1H),3.50(dd, J = 13.9, 7.0 Hz,1H),7.08-7.31(m, 5H), 7.49-7.60(m,4H), 7.72-7.78(m, 3H), 9.21(s,1H),12.34(brs, 1H) 2-377

(DMSO-d6-400)0.72(t, J = 7.4 Hz, 3H),1.37(sextet, J = 7.4 Hz,2H),1.55(d, J = 5.6 Hz, 1H), 1.92(t,J = 7.2 Hz, 2H), 1.97(d, J = 5.6Hz,1H), 3.23(dd, J = 13.9, 4.6 Hz, 1H),3.50(dd, J = 13.9, 7.0 Hz,1H),7.07-7.22(m, 5H), 7.49-7.54(m,2H), 7.56-7.60(m, 2H), 7.68(t,J = 6.3Hz, 1H), 7.73-7.78(m, 2H),9.23(s, 1H), 12.33(brs, 1H) 2-378

(DMSO-d6-400)1.37(d, J = 5.1 Hz, 1H), 1.94(d,J = 5.1 Hz, 1H), 2.69(s,6H),3.17(dd, J = 14.4, 5.1 Hz, 1H),3.40(dd, J = 14.4, 7.0 Hz,1H),6.17(t, J = 5.8 Hz, 1H), 7.05-7.10(m, 2H), 7.13-7.25(m,3H),7.49-7.54(m, 2H), 7.55-7.60(m,2H), 7.74-7.79(m, 2H), 9.73(s,1H),12.25(brs, 1H) 2-379

(DMSO-d6-400)0.50-0.61(m, 4H), 1.38-1.46(m,1H), 1.53(d, J = 6.0 Hz,1H),1.97(d, J = 6.0 Hz, 1H), 3.24(dd,J = 14.4, 5.1 Hz, 1H), 3.52(dd,J =14.4, 7.4 Hz, 1H), 7.08-7.24(m,5H), 7.49-7.54(m, 2H), 7.56-7.59(m, 2H),7.73-7.78(m, 2H),7.95(t, J = 6.0 Hz, 1H), 9.25(s,1H), 12.31(brs, 1H)2-380

(DMSO-d6-400)1.00-1.27(m, 5H), 1.44-1.66(m,5H), 1.54(d, J = 6.0 Hz, 1H),1.90-1.99(m, 1H), 1.96(d, J = 5.6 Hz,1H), 3.18(dd, J = 14.4, 4.6 Hz,1H),3.51(dd, J = 14.4, 7.4 Hz, 1H),7.06-7.23(m, 4H), 7.49-7.64(m,6H),7.73-7.78(m, 2H), 9.24(s,1H), 12.31(brs, 1H) 2-381

(DMSO-d6-400)1.46(d, J = 5.6 Hz, 1H), 1.96(d,J = 5.6 Hz, 1H),3.10-3.56(m, 10H),6.36(t, J = 5.8 Hz, 1H), 7.06-7.24(m, 5H), 7.52(d, J =8.8 Hz,2H), 7.57-7.58(m, 2H), 7.76(d,J = 8.3 Hz, 2H), 9.43(s,1H),12.28(brs, 1H) 2-382

(CDCl3-300)1.50(s, 3H), 1.83(d, J = 5.9 Hz,1H), 2.17(d, J = 5.9 Hz,1H),6.12(s, 1H), 6.79(t, J = 53.6 Hz,1H), 6.90(s, 1H), 7.02-7.10(m,2H),7.15-7.24(m, 3H), 7.41(d,J = 4.0 Hz, 1H), 7.58(d, J = 4.0 Hz,1H) 2-383

(CDCl3-300)1.42-1.97(m, 4H), 2.14-2.29(m,1H), 2.50-2.62(m, 1H),2.94-3.10(m, 2H), 5.96(s, 1H), 6.79(t,J = 53.9 Hz, 1H), 6.88(s, 1H),7.03-7.21(m, 4H), 7.44(d, J = 4.0 Hz,1H), 7.66(d, J = 4.0 Hz, 1H) 2-384

(MeOH-d4-300)1.13(t, J = 7.0 Hz, 3H), 1.92(d,J = 5.9 Hz, 1H), 2.14(d, J= 6.2 Hz,1H), 3.46(d, J = 14.3 Hz, 1H),3.57(d, J = 14.7 Hz, 1H),3.94(q,J = 7.2 Hz, 2H), 7.15-7.19(m, 5H),7.38(d, J = 4.0 Hz, 1H),7.43(d,J = 8.4 Hz, 2H), 7.57(d, J = 4.0 Hz,1H), 7.66(d, J = 8.4 Hz, 2H)2-385

(DMSO-d6-300)1.46-2.04(m, 6H), 3.09-3.54(m,2H), 3.64-3.81(m, 2H),3.96-4.10(m, 1H), 7.06-7.26(m, 5H),7.52(d, J = 8.4 Hz, 2H), 7.57(s,2H),7.76(d, J = 8.4 Hz, 2H),9.36(brs, 1H), 12.31(brs, 1H) 2-386

(DMSO-d6-300)1.68(d, J = 5.7 Hz, 1H), 2.06-2.15(m, 1H), 3.07(s, 3H),3.39(d,J = 10.5 Hz, 1H), 3.77(d, J = 10.5 Hz,1H), 7.10-7.26(m, 5H),7.52(d,J = 8.7 Hz, 2H), 7.56(d, J = 4.1 Hz,1H), 7.58(d, J = 4.1 Hz,1H),7.75(d, J = 8.7 Hz, 2H), 9.11(brs,1H), 12.29(brs, 1H) 2-387

(DMSO-d6-300)1.59(q, J = 5.3 Hz, 1H), 2.01(dd,J = 8.3, 5.3 Hz, 1H),2.72(t,J = 8.5 Hz, 1H), 3.87(s, 3H), 7.16-7.29(m, 6H), 7.48(d, J = 3.8Hz,1H), 7.84(s, 1H), 8.19(s, 1H),9.07(brs, 1H), 12.19(brs, 1H) 2-388

(MeOH-d4-300)1.97(dd, J = 9.8, 5.7 Hz, 1H),2.18(dd, J = 8.7, 6.0 Hz,1H),2.86(t, J = 9.2 Hz, 1H), 7.17-7.31(m, 5H), 7.63(d, J = 3.8 Hz,1H),7.66(d, J = 3.8 Hz, 1H),7.95(d, J = 9.0 Hz, 2H), 8.33(d,J = 9.0 Hz, 2H)2-389

(MeOH-d4-400)1.98-2.08(m, 1H), 2.17-2.27(m,1H), 2.32-2.46(m, 1H),2.90(d,J = 10.2 Hz, 1H), 3.16-3.28(m, 2H),6.65(d, J = 8.3 Hz, 1H),6.73(t,J = 7.4 Hz, 1H), 6.95(t, J = 7.7 Hz,1H), 7.31(d, J = 7..9 Hz,1H),7.38(d, J = 4.2 Hz, 1H), 7.47-7.41(m, 2H), 7.58(d, J = 4.2 Hz,1H),7.68-7.62(m, 2H) 2-390

(DMSO-d6-300)1.32-1.70(m, 5H), 2.32-2.56(m,2H), 2.75-2.88(m, 1H),6.95-7.02(m, 1H), 7.04-7.10(m, 2H),7.20-7.28(m, 1H), 7.21(d,J = 9.0 Hz,2H), 7.46(dd, J = 8.3,2.3 Hz, 1H), 7.62(d, J = 8.3 Hz, 1H),7.70(d, J =2.3 Hz, 1H), 7.79(d,J = 9.0 Hz, 2H), 8.25(s, 1H),8.58(s, 1H), 10.11(s,1H) 2-391

(DMSO-d6-300)1.22-1.79(m, 5H), 2.36-2.59(m,2H), 2.82-2.98(m, 1H),6.96-7.03(m, 1H), 7.05-7.14(m, 2H),7.30-7.39(m, 1H), 7.52(d,J = 8.7 Hz,2H), 7.59(d, J = 3.8 Hz,1H), 7.63(d, J = 3.8 Hz, 1H),7.75(d, J = 8.7 Hz,2H), 8.63(s,1H), 8.70(s, 1H), 10.14(s, 1H) 2-392

(DMSO-d6-300)1.08(t, J = 5.8 Hz, 6H), 1.85(d,J = 6.4 Hz, 1H), 2.26(d, J= 7.9 Hz,1H), 3.01-3.10(m, 1H), 3.12-3.23(m, 1H), 3.36-3.47(m,1H),7.20-7.28(m, 7H), 7.54(d,J = 9.0 Hz, 3H), 7.58-7.63(m, 2H),67.76(d,J = 9.0 Hz, 3H), 8.23(brs,1H), 8.42(brs, 1H), 9.15(s, 1H),12.57(s, 1H)2-393

(DMSO-d6-300)1.90(d, J = 6.8 Hz, 1H), 2.27(d,J = 6.8 Hz, 1H),3.18-3.35(m, 1H),3.59-3.72(m, 1H), 4.44-4.53(m,2H), 7.21-7.37(m, 5H),7.50-7.60(m, 4H), 7.77-7.80(m, 2H),7.79-7.87(m, 2H), 9.15(s, 1H) 2-394

(DMSO-d6-300)1.74(d, J = 6.0 Hz, 1H), 2.06(d,J = 6.0 Hz, 1H),3.50-3.60(m, 1H),3.73-3.82(m, 1H), 7.10-7.21(m,5H), 7.49-7.63(m, 4H),7.77(d,J = 8.7 Hz, 2H), 8.02-8.09(m, 1H),8.44-8.52(m, 1H), 8.71(dd, J =4.9,1.5 Hz, 1H), 8.81(d, J = 2.3 Hz, 1H),9.19(s, 1H) 2-395

(DMSO-d6-300)1.56(d, J = 6.0 Hz, 1H), 1.98(d,J = 6.0 Hz, 1H), 2.14(t, J= 6.8 Hz,2H), 3.16-3.26(m, 1H), 3.44-3.58(m, 3H), 4.49(t, J = 5.3Hz,1H), 7.09-7.25(m, 5H), 7.53(d,J = 8.9 Hz, 2H), 7.56-7.61(m,2H),7.70-7.80(m, 3H), 9.24(s, 1H),12.32(s, 1H) 2-396

(DMSO-d6-300)0.94(t, J = 6.8 Hz, 3H), 1.36(d,J = 6.4 Hz, 1H), 1.95(d, J= 6.4 Hz,1H), 2.91-3.03(m, 2H), 3.21(dd,J = 6.8, 3.4 Hz, 1H), 3.36(dd,J= 6.8, 3.4 Hz, 1H), 5.76-5.91(m,2H), 7.09-7.28(m, 2H), 7.52(d,J = 8.7Hz, 1H), 7.58(dd, J = 4.5,3.8 Hz, 1H), 7.77(d, J = 8.3 Hz, 2H),9.70(s,1H), 12.24(brs, 1H) 2-397

(DMSO-d6-300)0.87(d, J = 4.1 Hz, 3H), 0.89(d,J = 4.1 Hz, 3H), 1.57(d, J= 5.7 Hz,1H), 1.99(d, J = 6.0 Hz, 1H), 2.19-2.28(m, 1H), 3.25(dd, J =14.1,4.7 Hz, 1H), 3.50(dd, J = 13.6,6.8 Hz, 1H), 7.09-7.26(m,5H),7.51-7.69(m, 4H), 7.78(d,J = 8.7 Hz, 2H), 9.27(brs, 1H),12.34(brs,1H) 2-398

(DMSO-d6-300)1.62(d, J = 5.7 Hz, 1H), 2.02(d,J = 5.7 Hz, 1H), 3.28(dd, J= 12.8,3.4 Hz, 1H), 3.62-3.69(m, 6H),7.13-7.34(m, 5H), 7.52-7.67(m,4H),7.78(d, J = 8.3 Hz, 2H),9.35(brs, 1H), 12.36(brs, 1H) 2-399

(DMSO-d6-300)1.58(d, J = 5.7 Hz, 1H), 2.01(d,J = 6.4 Hz, 1H), 3.22(dd, J= 13.8,4.3 Hz, 1H), 3.66(d, J = 5.7 Hz, 2H)3.75(dd, J = 13.9, 7.9 Hz,1H),5.42(brs, 1H), 7.11-7.26(m, 5H),7.54(d, J = 8.7 Hz, 2H), 7.59(s,2H),7.69-7.81(m, 3H), 9.47(brs,1H), 12.33(brs, 1H) 2-400

(CDCl3-400)1.66(d, J = 6.5 Hz, 1H), 1.99-2.01(m, 1H), 2.15(d, J = 6.0Hz,1H), 2.97-3.01(m, 1H), 3.04(d,J = 14.8 Hz, 1H), 3.20-3.24(m,1H),3.51-3.53(m, 1H), 4.07(d,J = 17.2 Hz, 1H), 4.11(d, J = 14.8 Hz,1H),4.15(d, J = 17.2 Hz, 1H), 7.05-7.10(m, 2H), 7.19(d, J = 4.2 Hz,1H),7.24-7.26(m, 3H), 7.39(d,J = 8.3 Hz, 2H), 7.53(d, J = 8.3 Hz,2H),7.56(d, J = 3.7 Hz, 1H),8.82(brs, 1H) 2-401

(DMSO-d6-300)1.25(d, J = 6.4 Hz, 3H), 1.92(dd,J = 10.4, 6.6 Hz, 1H),2.70(d,J = 10.2 Hz, 1H), 7.17-7.29(m, 5H),7.45(s, 1H), 7.71(s, 1H),7.95(d,J = 8.7 Hz, 2H), 8.15(d, J = 8.7 Hz,2H), 8.94(brs, 1H),12.23(brs,1H) 2-402

(DMSO-d6-400)1.35-1.40(m, 4H), 2.02-2.07(m,4H), 7.11-7.24(m, 5H),7.41(d,J = 3.7 Hz, 1H), 7.49(d, J = 3.7 Hz,1H), 7.64(s, 2H), 9.11(brs,1H),10.11(brs, 1H), 12.10(brs, 1H) 2-403

(MeOH-d4-300)1.52(s, 3H), 1.76(d, J = 6.0 Hz,1H), 2.21(d, J = 6.0 Hz,1H),3.44(s, 3H), 4.60(s, 2H), 6.85(s,1H), 7.18-7.21(m, 5H), 7.55(d,J =4.1 Hz, 1H), 7.61(d, J = 4.1 Hz,1H) 2-404

(MeOH-d4-300)1.38(d, J = 6.8 Hz, 3H), 2.21(dd,J = 10.5, 6.8 Hz, 1H),2.94(d,J = 10.5 Hz, 1H), 3.45(s, 3H),4.61(s, 2H), 6.86(s, 1H),7.20-7.27(m, 5H), 7.56(d, J = 4.1 Hz,1H), 7.64(d, J = 4.1 Hz, 1H) 2-405

(DMSO-d6-300)1.58(d, J = 5.7 Hz, 1H), 2.10(d,J = 5.7 Hz, 1H), 3.65(d, J= 10.2 Hz,1H), 3.74(d, J = 10.2 Hz, 1H),3.80(d, J = 17.3 Hz, 1H),3.86(d,J = 17.3 Hz, 1H), 7.20(m, 5H),7.53(d, J = 8.7 Hz, 2H),7.57(s,2H), 7.75(d, J = 8.7 Hz, 2H) 2-406

(DMSO-d6-300)1.39(s, 4H), 2.09(d, J = 5.7 Hz,1H), 7.11-7.27(m, 5H),7.42(d,J = 8.3 Hz, 1H), 7.56-7.69(m, 3H),7.92(t, J = 8.5 Hz, 1H),9.25(brs,1H), 12.12(brs, 1H) 2-407

(DMSO-d6-300)1.26(d, J = 6.8 Hz, 3H), 1.92-2.05(m, 1H), 2.78(d, J = 10.5Hz,1H), 7.15-7.31(m, 5H), 7.42(dd,J = 8.7, 1.9 Hz, 1H), 7.58-7.69(m,3H),7.92(tt, J = 8.5 Hz, 1H),9.10(brs, 1H), 12.31(brs, 1H) 2-408

(MeOH-d4-300)1.28-1.40(m, 9H), 2.13-2.23(m,1H), 2.93(d, J = 9.0 Hz, 1H),3.05-3.17(m 1H), 6.57(s, 1H), 7.11-7.28(m, 5H), 7.51(d, J = 3.0 Hz,1H),7.61(d, J = 3.0 Hz, 1H) 2-409

(MeOH-d4-300)1.22(t, J = 7.5 Hz, 3H), 1.98(d,J = 6.0 Hz, 1H), 2.29(d, J= 6.0 Hz,1H), 2.86(d, J = 12.0 Hz, 1H), 2.99-3.13(m, 2H), 3.24(d, J =12.0 Hz,1H), 4.08(q, J = 8.0 Hz, 2H), 7.14-7.35(m, 5H), 7.61-7.68(m, 3H)2-410

(MeOH-d4-300)1.97(d, J = 6.0 Hz, 1H), 2.28(d,J = 6.0 Hz, 1H), 2.83(d, J= 15.0 Hz,1H), 2.98(d, J = 15.0 Hz, 1H),3.07(d, J = 12.0 Hz, 1H),3.24(d,J = 12.0 Hz, 1H), 7.13-7.31(m, 5H),7.61-7.68(m, 3H) 2-411

(DMSO-d6-400)1.58-1.67(m, 2H), 1.79-1.97(m,3H), 2.43-2.54(m, 1H),2.76(d,J = 9.7 Hz, 1H), 4.65(brs, 1H),7.01-7.27(m, 4H), 7.51(d,J = 8.3Hz, 2H), 7.54(d, J = 3.7 Hz,1H), 7.56(d, J = 3.7 Hz, 1H),7.73(d, J = 8.3Hz, 2H) 2-412

(DMSO-d6-400)1.20-1.36(m, 1H), 1.41-1.68(m,2H), 1.82-1.91(m, 1H),2.06-2.19(m, 1H), 2.43-2.55(m, 1H),2.64(d, J = 9.7 Hz, 1H), 4.99-5.04(m,1H), 7.06-7.12(m, 2H),7.16-7.22(m, 1H), 7.38(d,J = 7.4 Hz, 1H), 7.51(d,J = 8.3 Hz,2H), 7.54-7.57(m, 2H), 7.73(d,J = 8.3 Hz, 2H) 2-413

(DMSO-d6-300)1.36-1.43(m, 1H), 1.39(s, 3H),2.08(d, J = 5.3 Hz, 1H),7.11-7.27(m, 5H), 7.46-7.56(m, 1H),7.54(d, J = 4.1 Hz, 1H), 7.61(d,J =4.1 Hz, 1H), 7.68-7.76(m, 1H),8.00(dd, J = 6.8, 2.3 Hz, 1H),9.22(s, 1H),12.11(s, 1H) 2-414

(MeOH-d4-300)1.52(d, J = 8.3 Hz, 3H), 1.76(d,J = 5.7 Hz, 1H), 2.23(d, J= 5.7 Hz,1H), 7.11-7.25(m, 5H), 7.61(d,J = 4.1 Hz, 1H), 7.93(d, J = 4.1Hz,1H), 8.89(s, 2H) 2-415

(DMSO-d6-300)0.81(t, J = 6.2 Hz, 1H), 1.55(q,J = 5.3 Hz, 1H), 2.63(t, J= 8.9 Hz,1H), 3.69(q, J = 7.2 Hz, 1H),4.92(dd, J = 14.9, 5.1 Hz,1H),7.11-7.18(m, 2H), 7.24(t,J = 7.0 Hz, 1H), 7.35(d, J = 7.5 Hz,1H),7.52(d, J = 8.7 Hz, 2H),7.57(dd, J = 6.0, 4.1 Hz, 2H),7.74(d, J = 8.7Hz, 2H), 8.06(t,J = 5.5, 1H), 9.34(brs, 1H) 2-416

(DMSO-d6-300)1.38(s, 3H), 1.39(d, J = 6.4 Hz,1H), 2.08(d, J = 5.7 Hz,1H), 7.12-7.26(m, 5H), 7.55(d, J = 3.8 Hz,1H), 7.78(d, J = 3.8 Hz,1H),7.87(td, J = 8.7, 3.0 Hz, 1H),8.13(dd, J = 4.4, 2.2 Hz, 1H),8.60(d,J = 3.0 Hz, 1H), 9.19(brs,1H), 12.08(brs, 1H) 2-417

(CDCl3-400)1.44(d, J = 7.0 Hz, 3H), 2.35(s,3H), 2.49-2.51(m, 1H),3.06(d,J = 10.7 Hz, 1H), 6.33(brs, 1H),6.79(s, 1H), 7.22-7.28(m,6H),7.36(d, J = 4.2 Hz, 1H), 7.57(d,J = 4.2 Hz, 1H) 2-418

(CDCl3-400)2.07-2.10(m, 1H), 2.27-2.32(m,4H), 6.27(brs, 1H), 6.65(s,1H),7.17-7.24(m, 6H), 7.53(d,J = 4.2 Hz, 1H) 2-419

(DMSO-d4-300)1.35(d, J = 6.6 Hz, 3H) 2.16(dd,J = 10.5, 6.6 Hz, 1H),2.91(d,J = 10.5 Hz, 1H), 3.02(s, 6H), 7.17-7.23(m, 6H), 7.43(d, J = 4.0Hz,1H), 7.59(d, J = 4.0 Hz, 1H) 2-420

(DMSO-d6-300)1.39(s, 3H), 1.40(d, J = 3.4 Hz,1H), 2.09(d, J = 5.7 Hz,1), 7.12-7.26(m, 5H), 7.59-7.63(m, 3H),8.11(ddd, J = 8.9, 4.4, 2.2 Hz,1H),8.38(dd, J = 6.0, 2.3 Hz, 1H),9.25(brs, 1H), 12.12(brs, 1H) 2-421

(DMSO-d6-300)1.25(d, J = 5.7 Hz, 1H), 1.37(s,3H), 2.00(d, J = 5.3 Hz,1H), 3.11-3.19(m, 4H), 3.69-3.75(m, 4H),6.16(d, J = 4.5 Hz, 1H),7.14-7.23(m, 6H), 8.72(brs, 1H),12.03(brs, 1H) 2-422

(MeOH-d4-300)1.54(s, 3H), 1.79(d, J = 5.7 Hz,1H), 2.24(d, J = 5.7 Hz,1H), 6.96-7.08(m, 7H), 7.64(dd, J = 4.9,4.1 Hz, 2H) 2-423

(MeOH-d4-300)1.50(s, 3H), 1.72(d, J = 5.9 Hz,1H), 2.19(d, J = 5.9 Hz,1H),3.02(s, 6H), 5.47(s, 1H), 7.10-7.23(m, 5H), 7.42(d, J = 4.0 Hz,1H),7.56(d, J = 4.0 Hz, 1H) 2-424

(CDCl3-400)1.32(d, J = 6.7 Hz, 3H), 2.23(brs,1H), 3.00(d, J = 10.3 Hz,1H),3.48(s, 1H), 6.16(brs, 1H), 7.13-7.27(m, 6H), 7.46(d, J = 3.9 Hz,1H) 2-425

(CDCl3-400)1.34(d, J = 6.7 Hz, 3H), 2.25-2.36(m, 1H), 2.58(s, 3H),3.05(d,J = 10.5 Hz, 1H), 6.11(s, 1H), 7.16-77.29(m, 5H), 7.58(dd, J =3.9,18.4 Hz, 2H) 2-426

(CDCl3-400)1.34(d, J = 6.7 Hz, 3H), 2.19-2.28(m, 1H), 3.11-3.20(m,5H),3.36-3.43(m, 4H), 5.58(s, 1H),6.83(d, J = 8.9 Hz, 2H), 7.21-7.29(m,7H) 2-427

(CDCl3-400)1.32-1.35(m, 3H), 2.17-2.28(m,1H), 3.01(d, J = 10.3 Hz,1H),6.11(brs, 1H), 7.00(d, J = 4.0 Hz,1H), 7.18-7.32(m, 5H), 7.38(d,J =4.0 Hz, 1H) 2-428

(CDCl3-400)1.33-1.36(m, 3H), 2.21-2.29(m,1H), 3.17(d, J = 10.5 Hz, 1H),3.30-3.32(m, 4H), 3.40-3.42(m, 4H),5.59(s, 1H), 6.94(d, J = 8.6 Hz,2H),7.14-7.29(m, 5H), 7.50(d,J = 8.7 Hz, 2H) 2-429

(CDCl3-300)1.93(d, J = 5.9 Hz, 1H), 2.14(d,J = 5.9 Hz, 1H), 3.35-3.67(m,5H),3.38(s, 3H), 3.88(d, J = 9.5 Hz,1H), 7.11-7.25(m, 5H), 7.39(d,J =8.8 Hz, 2H), 7.54(d, J = 8.8 Hz,2H), 7.57(d, J = 3.7 Hz, 2H) 2-430

(MeOH-d4-400)1.86-1.96(m, 1H), 2.08-2.21(m,1H), 2.62-2.68(m, 1H),2.81(d,J = 9.7 Hz, 1H), 3.21-3.31(m, 2H),6.86-6.95(m, 2H), 7.17(t,J =7.7 Hz, 1H), 7.23(d, J = 7.4 Hz,1H), 7.40(d, J = 4.2 Hz, 1H),7.47-7.42(m, 2H), 7.60(d, J = 3.7 Hz,1H), 7.70-7.64(m, 2H) 2-431

(DMSO-d6-300)2.41(dd, J = 6.8, 7.2 Hz, 1H),2.95(d, J = 6.8 Hz, 1H),3.11(dd,J = 17.3, 7.2 Hz, 1H), 3.24-3.40(m,1H), 7.04-7.10(m, 3H),7.20-7.26(m, 1H), 7.53(d, J = 8.7 Hz,2H), 7.57(d, J = 3.8 Hz,1H),7.60(d, J = 3.8 Hz, 1H), 7.76(d,J = 8.7 Hz, 2H), 9.07(s,1H),12.10(s, 1H) 2-432

(MeOH-d4-300)1.77(s, 3H), 1.92(d, J = 6.0 Hz,1H), 2.25(d, J = 6.0 Hz,1H),2.93(d, J = 12.0 Hz, 1H), 3.05(d,J = 12.0 Hz, 1H), 7.12-7.28(m,5H),7.38(d, J = 3.0 Hz, 1H), 7.43(d,J = 9.0 Hz, 2H), 7.56(d, J = 3.0Hz,1H), 7.65(d, J = 9.0 Hz, 2H) 2-433

(MeOH-d4-300)0.90-0.94(m, 2H), 1.05-1.12(m,2H), 1.32(d, J = 6.6 Hz, 3H),2.09-2.15(m, 2H), 2.88(d, J = 10.6 Hz,1H), 6.44(s, 1H), 7.09-7.32(m,5H),7.43(d, J = 4.0 Hz, 1H),7.56(d, J = 4.0 Hz, 1H) 2-434

(DMSO-d6-300)1.39(s, 4H), 2.08(d, J = 5.7 Hz,1H), 7.11-7.27(m, 5H),7.53-7.71(m, 4H), 7.88(dd, J = 10.5,2.3 Hz, 1H), 9.24(brs,1H),12.14(brs, 1H) 2-435

(DMSO-d6-300)1.27(d, J = 6.4 Hz, 3H), 1.92-2.06(m, 1H), 2.78(d, J = 10.2Hz,1H), 7.13-7.31(m, 5H), 7.53-7.71(m, 4H), 7.87(dd, J = 10.5,1.9 Hz,1H), 9.10(brs, 1H),12.31(brs, 1H) 2-436

(CDCl3-400)0.94-1.03(m, 3H), 1.08-1.13(m,1H), 1.39-2.11(m, 13H),2.50-2.59(m, 1H), 5.94(brs, 1H),7.07(d, J = 7.4 Hz, 2H), 7.19-7.30(m,5H), 7.77-7.78(m, 2H) 2-437

(DMSO-d6-400)1.55-1.67(m, 2H), 1.80-1.99(m,3H), 2.42-2.54(m, 1H),2.77(d,J = 10.2 Hz, 1H), 4.66(brs, 1H),7.04(d, J = 6.5 Hz, 1H),7.10(dd,J = 7.0, 6.5 Hz, 1H), 7.16(dd,J = 7.0, 6.5 Hz, 1H), 7.23(d,J =6.5 Hz, 1H), 7.68(d, J = 3.7 Hz,1H), 7.85(d, J = 3.7 Hz, 1H),8.15(s, 1H)2-438

(DMSO-d6-400)1.55-1.67(m, 2H), 1.80-1.99(m,3H), 2.42-2.54(m, 1H),2.77(d,J = 10.2 Hz, 1H), 4.66(brs, 1H),7.04(d, J = 6.5 Hz, 1H),7.10(dd,J = 7.0, 6.5 Hz, 1H), 7.16(dd,J = 7.0, 6.5 Hz, 1H), 7.23(d,J =6.5 Hz, 1H), 7.68(d, J = 3.7 Hz,1H), 7.85(d, J = 3.7 Hz, 1H),8.15(s, 1H)2-439

(DMSO-d6-400)1.66-1.83(m, 2H), 1.88-2.00(m,1H), 2.49(s, 3H), 2.71(d,J =9.3 Hz, 1H), 2.94(ddd, J = 13.04.6, 2.8 Hz, 1H), 4.39(td, J = 12.5,5.6Hz, 1H), 7.15-7.21(m, 1H),7.25-7.37(m, 3H), 7.49-7.54(m,2H),7.55-7.59(m, 2H), 7.71-7.76(m, 2H), 9.11(brs, 1H),12.59(brs, 1H) 2-440

(MeOH-d4-300)2.31(d, J = 6.0 Hz, 1H), 2.34(s,3H), 2.48(d, J = 6.0 Hz,1H),3.42(d, J = 15.0 Hz, 1H), 3.95(d,J = 15.0 Hz, 1H), 7.13-7.46(m,8H),7.58(d, J = 3.0 Hz, 1H), 7.65(d,J = 9.0 Hz, 2H) 2-441

(CDCl3-400)1.24-1.42(m, 3H), 2.19(brs, 1H),2.56(s, 2H), 3.13(d, J = 11.3Hz,1H), 3.49(s, 2H), 3.93(s, 2H),5.64(brs, 1H), 6.01(s, 1H),7.24-7.31(m, 9H) 2-442

(CDCl3-400)0.90-0.94(m, 3H), 1.20-1.98(m,9H), 1.35(d, J = 6.5 Hz, 3H),2.28-2.30(m, 1H), 2.95-3.07(m, 4H),3.34-3.62(m, 4H), 3.88-3.94(m,2H),6.37(brs, 1H), 7.19-7.28(m,5H), 10.07(brs, 1H) 2-443

(DMSO-d6-300)1.19-1.39(m, 9H), 1.97-2.05(m,1H), 3.07-3.58(m, 7H),3.65-3.80(m, 2H), 6.21-6.31(m, 1H),7.09-7.31(m, 6H), 8.80(brs,1H),10.73(brs, 1H), 12.05(brs, 1H) 2-444

(DMSO-d6-300)1.26(d, J = 6.6 Hz, 3H), 2.00(dq,J = 10.3, 6.6 Hz, 1H),2.78(d,J = 10.3 Hz, 1H), 7.14-7.30(m, 5H),7.35(d, J = 4.0 Hz, 1H),7.50(d,J = 4.0 Hz, 1H), 7.93(s, 1H),8.87(s, 1H), 9.05(brs,1H),12.20(brs, 1H) 2-445

(DMSO-d6-400)1.25(d, J = 7.0 Hz, 3H), 2.04(ddJ = 10.4, 6.7 Hz, 1H),2.93(d,J = 10.2 Hz, 1H), 3.82(t, J = 5.6 Hz,2H), 4.31(t, J = 5.6 Hz,2H),4.48(brs, 1H), 4.70(s, 2H), 7.16-7.32(m, 5H), 7.42(dd, J = 8.8,1.9Hz, 1H), 7.71(d, J = 8.3 Hz, 1H),7.80(d, J = 1.9 Hz, 1H), 8.81(s,1H),12.29(brs, 1H) 2-446

(DMSO-d6-300)2.20(dd, J = 6.4, 7.2 Hz, 1H),2.78(d, J = 6.4 Hz, 1H),3.03(dd,J = 17.3, 7.2 Hz, 1H), 3.19-3.44(m,1H), 5.22(s, 2H),7.01-7.09(m,3H), 7.16-7.22(m, 1H), 7.20(d,J = 9.0 Hz, 2H), 7.48(dd, J =8.3,2.3 Hz, 1H), 7.63(d, J = 8.3 Hz, 1H),7.;71(d, J = 2.3 Hz, 1H),7.75(d,J = 9.0 Hz, 2H), 8.61(brs, 1H) 2-447

(DMSO-d6-300)2.23(dd, J = 7.2, 7.3 Hz, 1H),2.78(d, J = 7.2 Hz, 1H),3.06(dd,J = 17.9, 7.3 Hz, 1H), 3.22-3.40(m,1H), 7.00-7.11(m, 3H),7.19-7.26(m, 1H), 7.53(d, J = 8.7 Hz,2H), 7.62(d, J = 4.1 Hz,1H),7.66(d, J = 4.1 Hz, 1H), 7.77(d,J = 8.7 Hz, 2H), 8.48(s,1H),8.74(brs, 1H), 9.92(s, 1H) 2-448

(DMSO-d6-300)1.37-1.43(m, 1H), 1.40(s, 3H),2.10(d, J = 5.7 Hz, 1H),7.12-7.27(m, 5H), 7.56(d, J = 3.8 Hz,1H), 7.65(t, J = 1.9 Hz,1H),7.73(d, J = 3.8 Hz, 1H), 7.81(d,J = 1.9 Hz, 2H), 9.26(d,1H),12.11(brs, 1H) 2-449

(DMSO-d6-400)1.36-1.38(m, 1H), 1.37(s, 3H),2.06(d, J = 5.1 Hz, 1H),6.07(s,2H), 6.97(d, J = 7.9 Hz, 1H), 7.11-7.25(m, 6H), 7.32(d, J = 1.9Hz,1H), 7.40(d, J = 3.7 Hz, 1H),7.47(d, J = 3.7 Hz, 1H), 9.11(s,1H),12.10(s, 1H) 2-450

(DMSO-d6-400)1.23(d, J = 6.5 Hz, 3H), 1.93(dd,J = 10.4, 6.7 Hz, 1H),2.73(d,J = 10.2 Hz, 1H), 3.70(s, 3H), 7.14-7.20(m, 3H), 7.22-7.27(m,3H),7.47(d, J = 3.7 Hz, 1H), 7.77(s,1H), 7.97(s, 1H), 8.92(s,1H),12.27(brs, 1H) 2-451

(DMSO-d6-400)1.25(d, J = 7.0 Hz, 3H), 1.99(dd,J = 10.4, 6.7 Hz, 1H),2.65(s, 3H),2.78(d, J = 10.7 Hz, 1H), 7.14-7.20(m, 3H), 7.22-7.28(m,2H),7.62(t, J = 2.1 Hz, 1H), 7.75(q,J = 1.9 Hz, 1H), 9.25(brs,1H),12.31(brs, 1H) 2-452

(DMSO-d6-300)1.39(s, 4H), 2.07(d, J = 5.3 Hz,1H), 5.30(brs, 2H),6.56-6.61(m,1H), 6.80-6.88(m, 2H), 7.04-7.27(m, 6H), 7.34(d, J = 4.1Hz,1H), 7.50(d, J = 3.8 Hz, 1H),9.11(brs, 1H), 12.11(brs, 1H) 2-453

(DMSO-d6-400)1.40(s, 4H), 2.09(d, J = 5.5 Hz,1H), 3.05(s, 3H),7.11-7.27(m,6H), 7.39-7.50(m, 4H), 7.54(d,J = 4.0 Hz, 1H), 9.18(brs,1H),9.91(brs, 1H), 12.10(brs, 1H) 2-454

(DMSO-d6-300)1.19(d, J = 6.0 Hz, 3H), 1.78-1.94(m, 3H), 2.68(d, J = 9.7Hz,1H), 3.06-3.19(m, 2), 3.28-3.41(m, 2H), 3.53(t, J = 5.8 Hz,2H),3.59(t, J = 5.1 Hz, 2H),6.71(d, J = 9.3 Hz, 2H), 7.10-7.19(m, 5H),7.23(d, J = 7.0 Hz,2H), 8.10(s, 1H) 2-455

(DMSO-d6-400)1.27(d, J = 5.1 Hz, 1H), 1.36(s,3H), 2.00(d, J = 5.6 Hz,1H), 2.03-2.13(m, 4H), 3.28-3.33(m, 4H),6.19(d, J = 4.2 Hz, 1H),7.12-7.16(m, 3H), 7.20-7.23(m, 3H),8.71(brs, 1H), 12.01(brs, 1H) 2-456

(DMSO-d6-400)1.25(d, J = 7.0 Hz, 3H), 1.99(dd,J = 10.4, 6.7 Hz, 1H),2.78(d,J = 10.7 Hz, 1H), 7.14-7.27(m, 5H),7.68(d, J = 4.2 Hz, 1H),7.82-7.90(m, 2H), 8.09(ddd, J = 11.6,7.7, 1.9 Hz, 2H), 8.20(d, J = 4.2Hz,1H), 9.18(brs, 1H), 9.62(s, 1H),12.32(brs, 1H) 2-457

(MeOH-d4-400)1.36(d, J = 6.8 Hz, 3H), 2.13-2.20(m, 1H), 3.03(d, J = 10.5Hz,1H), 3.30-3.35(m, 4H), 3.58-3.61(m, 4H), 6.81-8.06(m, 8H) 2-458

(MeOH-d4-400)1.35-1.38(m, 3H), 2.12-2.20(m,1H), 3.03(d, J = 10.4 Hz,1H), 3.20-3.23(m, 4H), 3.35-3.38(m, 4H),6.88-6.91(m, 2H),7.16-7.34(m,8H) 2-459

(CDCl3-400)1.34(d, J = 7.0 Hz, 3H), 2.21-2.29(m, 1H), 3.15-3.21(m,5H),3.37-3.40(m, 4H), 5.56(s, 1H),6.64(ddd, J = 2.7, 10.4, 11.6 Hz,2H),7.20-7.30(m, 6H) 2-460

(MeOH-d4-400)1.36(d, J = 7.0 Hz, 3H), 2.14-2.22(m, 1H), 3.04(d, J = 10.5Hz,1H), 3.10-3.12(m, 4H), 3.37-3.40(m, 4H), 6.99-7.33(m, 8H) 2-461

(CDCl3-400)1.20-1.32(m, 2H), 1.33(d,J = 6.5 Hz, 3H), 1.97-2.12(m,2H),2.24-2.35(m, 1H), 2.99(d,J = 10.2 Hz, 1H), 3.29-3.92(m,6H),6.04(brs, 1H), 6.83(dd, J = 9.7,1.9 Hz, 1H), 7.114-7.33(m,5H),7.71(dt, J = 9.7, 2.3 Hz, 1H),7.92(t, J = 2.3 Hz, 1H) 2-462

(CDCl3-400)1.21-1.30(m, 2H), 1.33(d,J = 6.5 Hz, 3H), 1.97-2.11(m,2H),2.25-2.35(m, 1H), 2.99(d,J = 10.7 Hz, 1H), 3.28-3.94(m,6H),6.01(brs, 1H), 6.81-6.87(m, 1H),7.13-7.31(m, 5H), 7.62-7.69(m,1H),7.87(s, 1H) 2-463

(CDCl3-400)1.31(d, J = 7.0 Hz, 3H), 2.25(dq,J = 10.7, 7.0 Hz, 1H),3.10(d,J = 10.7 Hz, 1H), 3.47-3.59(m, 4H),3.77-3.89(m, 4H), 6.31(brs,1H),7.13-7.33(m, 6H), 7.41-7.46(m,1H), 7.53-7.64(m, 2H) 2-464

(CDCl3-400)1.35(d, J = 7.0 Hz, 3H), 2.27(dq,J = 10.2, 7.0 Hz, 1H),3.13(d,J = 10.2 Hz, 1H), 3.41-3.49(m, 4H),3.76-3.86(m, 4H), 6.18(brs,1H),7.11-7.35(m, 9H) 2-465

(CDCl3-400)1.37(d, J = 7.0 Hz, 3H), 2.29-2.33(m, 1H), 2.59(s, 3H),3.46(t,J = 4.9 Hz, 4H), 3.63(t, J = 4.9 Hz,4H), 5.98(brs, 1H),7.21-7.32(m,5H) 2-466

(DMSO-d6-300)1.39(s, 3H), 1.40(d, J = 4.9 Hz,1H), 2.10(d, J = 5.7 Hz,1H), 7.16-7.25(m, 5H), 7.60(d, J = 4.1 Hz,1H), 7.65-7.68(m, 1H),8.13-8.19(m, 1H), 8.60(d, J = 2.3 Hz,1H), 9.27(brs, 1H), 12.10(brs,1H)2-467

(DMSO-d6-300)1.24(d, J = 5.3 Hz, 1H), 1.37(s,3H), 2.00(d, J = 5.3 Hz,1H), 2.59-2.61(m, 1H), 3.49(t, J = 7.2 Hz,2H), 3.73(t, J = 12.8 Hz,2H),5.90(d, J = 4.1 Hz, 1H), 7.14-7.26(m, 6H), 8.69(brs, 1H),12.02(brs,1H) 2-468

(DMSO-d6-300)1.26(d, J = 6.4 Hz, 3H), 1.98(dd,J = 10.4, 6.6 Hz, 1H),2.78(d,J = 10.5 Hz, 1H), 7.14-7.30(m, 6H),7.45(d, J = 3.8 Hz, 1H),7.54(d,J = 3.8 Hz, 1H), 7.61(dd, J = 8.3,1.9 Hz, 1H), 8.00(d, J = 1.9Hz, 1H),9.01(brs, 1H), 12.22(brs, 1H) 2-469

(DMSO-d6-300)1.28(d, J = 6.4 Hz, 3H), 2.01(dd,J = 10.2, 6.8 Hz, 1H),2.81(d,J = 10.2 Hz, 1H), 2.83(s, 3H), 7.16-7.31(m, 5H), 7.58(d, J = 3.8Hz,1H), 7.65(d, J = 4.1 Hz, 1H),7.71(dd, J = 8.5, 1.7 Hz, 1H),8.12(d, J= 8.7 Hz, 1H), 8.24(d,J = 1.5 Hz, 1H), 9.05(s, 1H),12.31(brs, 1H) 2-470

(DMSO-d6-300)1.26(d, J = 6.8 Hz, 3H), 1.97(dd,J = 10.5, 6.8 Hz, 1H),2.77(d,J = 10.5 Hz, 1H), 6.08(s, 2H),6.99(d, J = 7.9 Hz, 1H),7.15-7.30(m, 6H), 7.33(d, J = 1.5 Hz,1H), 7.41(d, J = 3.8 Hz,1H),7.50(d, J = 3.8 Hz, 1H), 8.98(brs,1H), 12.30(brs, 1H) 2-471

(DMSO-d6-300)1.21(d, J = 6.0 Hz, 3H), 1.80-2.01(m, 3H), 2.70(d, J = 11.3Hz,1H), 3.10-3.21(m, 2H), 3.30-3.43(m, 2H), 3.51-3.66(m,4H),6.53-6.78(m, 3H), 7.09-7.30(m,6H), 8.13(s, 1H) 2-472

(DMSO-d6-300)1.22(d, J = 6.8 Hz, 3H), 1.81-2.00(m, 3H), 2.71(d, J = 10.9Hz,1H), 3.10-3.19(m, 2H), 3.32-3.43(m, 2H), 3.48-3.65(m,4H),6.65-6.77(m, 2H), 6.92-7.02(m,2H), 7.12-7.30(m, 5H), 8.11(s,1H)2-473

(DMSO-d6-300)1.39-1.52(m, 1H), 1.91-2.00(m,1H), 2.61-2.71(m, 1H),7.11-7.28(m, 5H), 7.49-7.65(m, 3H),7.77(d, J = 8.7 Hz, 2H), 7.91-8.01(m,4H), 8.78(s, 1H),10.58(s, 1H), 12.07(s, 1H) 2-474

(DMSO-d6-300)1.41-1.51(m, 1H), 1.92-2.01(m,1H), 2.64-2.74(m, 2H),7.10-7.29(m, 6H), 7.37(t, J = 8.1 Hz,2H), 7.77(d, J = 8.1 Hz,2H),7.93(d, J = 8.3 Hz, 2H), 8.11(d,J = 8.3 Hz, 2H), 9.05(s,1H),10.42(s, 2H), 12.16(s, 1H) 2-475

(DMSO-d6-300)1.26(d, J = 6.8 Hz, 3H), 1.93-2.07(m, 1H), 2.86(d, J = 10.2Hz,1H), 3.11-3.19(m, 2H), 3.20-3.27(m, 2H), 3.28-3.34(m, 4H),6.05(s,1H), 7.12-7.31(m, 5H),8.31(s, 1H), 12.37(s, 1H) 2-476

(DMSO-d6-300)1.26(d, J = 7.5 Hz, 3H), 1.98-2.11(m, 1H), 2.91(d, J = 9.8Hz,1H), 3.51-3.62(m, 3H), 3.82-3.93(m, 2H), 3.96(s, 2H), 6.80(s,1H),7.13-7.32(m, 5H), 8.66(s,1H), 12.47(s, 1H) 2-477

(DMSO-d6-300)1.39(s, 3H), 1.42(d, J = 5.7 Hz,1H), 2.08(d, J = 4.9 Hz,1H), 7.12-7.25(m, 5H), 7.58(d, J = 4.1 Hz,1H), 7.74(d, J = 3.8 Hz,1H),7.84(d, J = 8.7 Hz, 1H), 8.03(dd,J = 8.7, 2.3 Hz, 1H), 8.44(d,J =2.3 Hz, 1H), 9.29(brs, 1H),12.16(brs, 1H) 2-478

(DMSO-d6-300)1.34-1.42(m, 1H), 1.35(t,J = 7.2 Hz, 3H), 1.40(s,3H),2.09(d, J = 5.3 Hz, 1H), ,4.36(q,J = 7.2 Hz, 2H), 7.10-7.28(m,5H),7.56(d, J = 3.8 Hz, 1H), 7.61-7.65(m, 1H), 7.64(d, J = 3.8 Hz,1H),7.94-8.04(m, 2H), 8.18(brs,1H), 9.25(s, 1H), 12.14(s, 1H) 2-479

(DMSO-d6-300)1.40(s, 3H), 1.42(d, J = 5.7 Hz,1H), 2.10(d, J = 5.7 Hz,1H), 7.13-7.27(m, 5H), 7.55-7.63(m, 1H),7.56(d, J = 4.1 Hz, 1H),7.62(d,J = 4.1 Hz, 1H), 7.93-8.00(m, 2H),8.15-8.18(m, 1H), 9.22(s, 1H)2-480

(DMSO-d6-300)1.37-1.41(m, 4H), 2.06(s, 3H),2.09(d, J = 5.7 Hz, 1H),7.13-7.27(m, 5H), 7.36-7.41(m, 2H),7.44(d, J = 3.8 Hz, 1H), 7.53-7.56(m,1H), 7.54(d, J = 3.8 Hz,1H), 7.97(brs, 1H), 9.18(s, 1H),10.08(s, 1H),12.11(brs, 1H) 2-481

(DMSO-d6-400)1.64(q, J = 5.1 Hz, 1H), 1.97(t,J = 7.2 Hz, 1H), 2.10(s,3H),2.69(t, J = 8.6 Hz, 1H), 7.11-7.24(m, 5H), 7.72(s, 1H), 7.98(d,J =8.8 Hz, 1H), 8.24(dd, J = 8.8,2.3 Hz, 1H), 8.44(s, 1H), 8.73(d,J = 2.3Hz, 1H), 12.20(brs, 1H) 2-482

(CDCl3-300)1.67(dd, J = 9.6, 5.5 Hz, 1H),2.04(dd, J = 8.5, 5.5 Hz,1H),2.79(t, J = 9.4 Hz, 1H), 3.80(s,3H), 7.15-7.29(m, 5H), 7.76(s,1H),8.00(d, J = 8.7 Hz, 1H),8.25(dd, J = 8.9, 2.4 Hz, 1H),8.36(s, 1H),8.73(d, J = 2.3 Hz,1H), 9.19(s, 1H), 12.30(brs, 1H) 2-483

(CDCl3-400)1.39(d, J = 7.0 Hz, 4H), 2.31(dd,J = 10.0, 6.7 Hz, 1H),2.68(s, 3H),3.15(d, J = 10.2 Hz, 1H), 3.23-3.24(m, 4H), 3.48-3.49(m,4H),6.10(brs, 1H), 6.94(dd, J = 8.8,2.3 Hz, 1H), 7.19-7.31(m,5H),7.53(d, J = 2.3 Hz, 1H), 7.59(d,J = 8.8 Hz, 1H) 2-484

(CDCl3-400)1.41(d, J = 7.0 Hz, 3H), 2.23(d,J = 1.4 Hz, 3H), 2.30-2.35(m,1H),3.09(d, J = 10.7 Hz, 1H), 3.41-3.46(m, 8H), 6.07(brs, 1H),6.62(d, J= 0.9 Hz, 1H), 7.26-7.30(m, 5H) 2-485

(DMSO-d6-300)1.36(s, 3H), 1.43(d, J = 4.9 Hz,1H), 1.99(d, J = 4.9 Hz,1H),4.28(s, 4H), 6.92(d, J = 8.3 Hz,1H), 7.07-7.24(m, 7H), 7.38(d,J =3.8 Hz, 1H), 7.48(d, J = 3.8 Hz,1H) 2-486

(DMSO-d6-300)1.73-1.92(m, 2H), 2.08-2.55(m,4H), 6.91-6.99(m, 1H),7.01-7.16(m, 3H), 7.77(d, J = 3.8 Hz,1H), 7.91(d, J = 3.8 Hz,1H),8.18(s, 1H), 8.70(s, 1H),8.90(brs, 1H), 9.80(s, 1H) 2-487

(DMSO-d6-300)1.37(s, 3H), 1.41(d, J = 5.1 Hz,1H), 2.07(d, J = 5.6 Hz,1H), 7.07-7.22(m, 6H), 7.34(d, J = 10.2 Hz,1H), 7.41-7.48(m, 2H),7.58-7.63(m, 2H), 9.10(brs, 1H),12.26(brs, 1H) 2-488

(DMSO-d6-300)1.38(d, J = 5.3 Hz, 1H), 1.39(s,3H), 2.09(d, J = 5.3 Hz,1H),2.79(s, 6H), 7.14-7.27(m, 5H),7.30(dd, J = 8.1, 2.1 Hz, 1H),7.37(d,J = 2.3 Hz, 1H), 7.45(d,J = 8.3 Hz, 1H), 7.54(d, J = 4.1 Hz,1H), 7.58(d,J = 3.8 Hz, 1H),9.18(s, 1H), 12.10(brs, 1H) 2-489

(DMSO-d6-400)1.68(dd, J = 10.2, 5.1 Hz, 1H),1.95(dd, J = 8.3, 5.1 Hz,1H),2.59(t, J = 9.3 Hz, 1H), 7.09-7.21(m, 5H), 7.25-7.31(m,1H),7.37-7.43(m, 2H), 7.81-7.86(m,2H), 8.23(s, 1H), 8.58(s, 1H) 2-490

(DMSO-d6-400)1.67(dd, J = 9.7, 5.1 Hz, 1H),1.96(dd, J = 8.3, 5.1 Hz,1H),2.61(t, J = 9.0 Hz, 1H), 7.08-7.24(m, 5H), 7.446(d, J = 8.8 Hz,2H),7.86(d, J = 8.8 Hz, 2H),8.27(s, 1H), 8.60(s, 1H) 2-491

(DMSO-d6-400)1.69(dd, J = 9.7, 5.6 Hz, 1H),1.98(dd, J = 8.6, 5.3 Hz,1H),2.64(t, J = 9.0 Hz, 1H), 7.11-7.27(m, 7H), 7.84-7.91(m, 2H),8.21(s,1H), 8.60(s, 1H) 2-492

(MeOH-d4-300)1.38(d, J = 6.8 Hz, 3H), 2.15-2.25(m, 1H), 2.93(d, J = 10.5Hz,1H), 3.81(s, 3H), 7.05(d,J = 4.1 Hz, 1H), 7.20-7.24(m,5H),7.47-7.49(m, 2H), 7.97(d,J = 0.8 Hz, 1H) 2-493

(DMSO-d6-300)1.27(d, J = 6.8 Hz, 3H), 1.99(dd,J = 10.9, 6.8 Hz, 1H),2.79(d,J = 10.9 Hz, 1H), 6.86(d, J = 1.5 Hz,1H), 7.02(t, J = 7.0 Hz,1H), 7.11-7.30(m, 6H), 7.39(d, J = 8.3 Hz,1H), 7.48(d, J = 3.8 Hz, 1H),7.51-7.58(m, 2H), 9.03(brs, 1H),11.73(brs, 1H), 12.32(brs, 1H) 2-494

(MeOH-d4-300)1.36(d, J = 9.0 Hz, 3H), 2.14-2.26(m, 1H), 2.93(d, J = 9.0Hz,1H), 7.12-7.28(m, 6H), 7.49(d,J = 3.0 Hz, 1H), 7.69(s, 1H),8.41(s,1H) 2-495

(DMSO-d6-300)2.26(dd, J = 6.8, 7.3 Hz, 1H),2.81(d, J = 6.8 Hz, 1H),3.08(dd,J = 17.5, 7.3 Hz, 1H), 3.26-3.38(m,1H), 7.01-7.11(m, 3H),7.20-7.29(m, 1H), 7.76(d, J = 3.8 Hz,1H), 7.89(d, J = 3.8 Hz,1H),8.17(s, 1H), 8.46(s, 1H),8.96(brs, 1H), 9.97(s, 1H) 2-496

(MeOH-d4-300)1.42(d, J = 6.8 Hz, 3H), 2.20(dd,J = 10.0, 7.0 Hz, 1H),2.93(d,J = 10.2 Hz, 1H), 6.90(dd, J = 8.3,1.9 Hz, 1H), 7.10(d, J = 1.9Hz, 1H),7.18-7.32(m, 7H), 7.56(d,J = 4.1 Hz, 1H) 2-497

(DMSO-d6-300)1.27(d, J = 6.8 Hz, 3H), 2.01(dd,J = 10.4, 6.6 Hz, 1H),2.80(d,J = 10.5 Hz, 1H), 7.15-7.29(m, 5H),7.62(d, J = 4.1 Hz, 1H),7.83(d,J = 3.8 Hz, 1H), 8.09(t, J = 4.7 Hz,1H), 8.17(d, J = 9.0 Hz,1H),8.45(s, 1H), 9.12(brs, 1H),12.31(brs, 1H) 2-498

(DMSO-d6-300)1.40(s, 3H), 1.42(d, J = 5.7 Hz,1H), 2.09(d, J = 5.7 Hz,1H), 7.10-7.28(m, 5H), 7.35(d, J = 4.1 Hz,1H), 7.49(d, J = 4.1 Hz,1H),7.94(s, 1H), 8.88(s, 1H),9.20(brs, 1H), 12.08(brs, 1H) 2-499

(DMSO-d6-400)1.24(d, J = 6.5 Hz, 3H), 1.94(dq,J = 10.4, 6.7 Hz, 1H),2.66(d,J = 10.7 Hz, 1H), 7.04-7.21(m, 5H),7.26-7.32(m, 1H),7.38-7.43(m,2H), 7.82-7.86(m, 2H), 8.23(s,1H), 8.56(s, 1H) 2-500

(CDCl3-400)1.27-1.31(m, 3H), 2.16(m, 3H),3.11(dd, J = 10.5, 16.6 Hz,1H),3.45-3.63(m, 4H), 4.85(s, 1H),5.71(brs, 1H), 6.71(m, 2H),7.16-7.30(m, 7H) 2-501

(CDCl3-400)1.29-1.34(m, 3H), 2.17(m, 3H),3.14(dd, J = 11.1, 19.9 Hz,1H),3.49-3.74(m, 4H), 4.89(s, 1H),5.65(brs, 1H), 6.65-7.00(m,2H),7.13-7.25(m, 7H) 2-502

(MeOH-d4-400)1.38(d, J = 6.7 Hz, 2H), 2.17-2.24(m,1H), 3.04(d, J = 10.5Hz, 1H), 3.70-3.71(m, 2H), 3.73-3.81(m, 2H),4.02-4.11(m, 2H),7.17-7.33(m,7H), 7.41-7.45(m, 2H) 2-503

(MeOH-d4-400)1.36(d, J = 6.7 Hz, 3H), 2.10-2.16(m,1H), 2.93(d, J = 10.4Hz, 1H), 3.37-3.39(m, 4H), 3.71(3.74(m, 4H),7.14-7.47(m, 7H) 2-504

(MeOH-d4-400)1.39(d, J = 6.67 Hz, 3H), 2.21(qd,J = 6.4, 12.9 Hz, 1H),3.05(d,J = 10.5 Hz, 1H), 3.72-3.74(m, 2H),3.86(t, J = 5.2 Hz, 2H),4.05-4.14(m, 2H), 7.17-7.30(m, 5H),7.55(d, J = 8.4 Hz, 2H), 7.73(d,J =8.4 Hz, 2H) 2-505

(MeOH-d4-400)1.35-1.38(m, 3H), 2.07(s, 1H),2.84(d, J = 10.4 Hz, 1H),4.57-4.73(m, 4H), 7.12-7.45(m, 8H) 2-506

(MeOH-d4-400)1.51(s, 3H), 1.70(d, J = 5.5 Hz,1H), 2.17(d, J = 5.5 Hz,1H), 7.17-7.21(m, 5H), 8.01(s, 4H), 8.02(s,1H), 8.90(s, 1H) 2-507

(MeOH-d4-400)1.35(d, J = 7.0 Hz, 3H), 2.15(qd,J = 6.7, 13.4 Hz, 1H),2.87(d,J = 10.5 Hz, 1H), 7.14-7.20(m, 1H),7.23(d, J = 4.3 Hz, 4H),8.03(s,5H), 8.90(s, 1H) 2-508

(DMSO-d6-300)1.19(d, J = 6.8 Hz, 3H), 1.85(dq,J = 10.2, 6.8 Hz, 1H),2.66(d,J = 10.2 Hz, 1H), 4.18(s, 2H),6.90(d, J = 3.8 Hz, 1H),7.04-7.35(m, 10H), 7.40(d, J = 3.8 Hz,1H) 2-509

(DMSO-d6-300)1.24(d, J = 6.4 Hz, 3H), 1.96(dq,J = 10.2, 6.4 Hz, 1H),2.73(d,J = 10.2 Hz, 1H), 6.79(d, J = 7.2 Hz,1H), 6.90-7.29(m, 8H),7.43(d,J = 3.8 Hz, 1H), 7.53(d, J = 3.8 Hz,1H) 2-510

(DMSO-d6-300)1.19(d, J = 5.7 Hz, 6H), 1.72(dd,J = 9.6, 5.3 Hz, 1H),2.02(dd,J = 9.4, 5.3 Hz, 1H), 2.74(t,J = 9.4 Hz, 1H), 2.95-3.11(m,4H),3.35-3.44(m, 4H), 4.74-4.82(m,1H), 7.12-7.30(m, 5H), 8.47(s,1H),12.25(s, 1H) 2-511

(DMSO-d6-300)0.86(d, J = 6.4 Hz, 6H), 1.24-1.35(m, 2H), 1.50-1.62(m,1H),1.71(dd, J = 5.5, 2.4 Hz, 1H),2.01(dd, J = 9.0, 5.5 Hz, 1H),2.24-2.32(m, 2H), 2.34-2.44(m, 4H),2.73(t, J = 9.0 Hz, 1H), 2.95-3.11(m,4H), 7.10-7.31(m, 5H),8.34(s, 1H) 2-512

(DMSO-d6-300)1.00(t, J = 7.2 Hz, 3H), 1.72(dd,J = 5.1, 8.5 Hz, 1H),2.01(dd,J = 8.5, 5.1 Hz, 1H), 2.72(t,J = 8.5 Hz, 1H), 2.92-3.11(m,6H),3.24-3.38(m, 4H), 6.53(t,J = 5.3 Hz, 1H), 7.13-7.31(m, 5H),8.42(s,1H), 12.28(s, 1H) 2-513

(DMSO-d6-300)0.89(d, J = 6.8 Hz, 6H), 1.71(dd,J = 8.9, 5.7 Hz, 1H),1.92-2.06(m,2H), 2.20(d, J = 6.8 Hz, 2H),2.75(t, J = 8.9 Hz, 1H),2.90-3.12(m, 4H), 3.42-3.61(m, 4H),7.13-7.32(m, 5H), 12.27(s,1H),12.27(s, 1H) 2-514

(DMSO-d6-300)1.27(d, J = 6.8 Hz, 3H), 2.01(dq,J = 10.2, 6.8 Hz, 1H),2.79(d,J = 10.2 Hz, 1H), 7.11-7.31(m, 6H),7.54(d, J = 4.1 Hz, 1H),7.55(d,J = 4.1 Hz, 1H), 8.80(s, 1H),9.13(brs, 1H), 12.31(brs, 1H) 2-515

(DMSO-d6-300)1.31(d, J = 5.3 Hz, 1H), 1.37(s,3H), 2.02(d, J = 5.3 Hz,1H),3.34(s, 3H), 6.21(d, J = 4.1 Hz,1H), 7.17-7.22(m, 7H), 7.33-7.42(m,4H), 8.71(brs, 1H),12.04(brs, 1H) 2-516

(DMSO-d6-300)1.39(s, 3H), 1.41(d, J = 4.1 Hz,1H), 2.08(d, J = 6.0 Hz,1H),3.95(s, 3H), 7.13-7.24(m, 5H),7.28(dd, J = 8.3, 1.9 Hz, 1H),7.41(d,J = 1.9 Hz, 1H), 7.50(d,J = 8.3 Hz, 1H), 7.55(d, J = 3.8 Hz,1H), 7.63(d,J = 3.8 Hz, 1H),9.17(brs, 1H), 12.13(brs, 1H) 2-517

(DMSO-d6-300)1.28(d, J = 6.8 Hz, 3H), 2.02(dd,J = 10.4, 6.6 Hz, 1H),2.81(d,J = 10.5 Hz, 1H), 7.14-7.30(m, 5H),7.65(d, J = 4.1 Hz, 1H),7.89(d,J = 4.1 Hz, 1H), 8.02(d, J = 10.2 Hz,1H), 8.17(d, J = 9.4 Hz,1H),8.45(s, 1H), 9.18(s, 1H),12.31(brs, 1H) 2-518

(DMSO-d6-400)1.42(s, 3H), 1.48(d, J = 5.6 Hz,1H), 2.13(d, J = 5.6 Hz,1H), 7.13-7.30(m, 6H), 7.40(t, J = 7.7 Hz,2H), 7.84(d, J = 7.4 Hz,2H),8.23(s, 1H), 8.59(s, 1H),9.52(brs, 1H), 12.24(brs, 1H) 2-519

(DMSO-d6-400)1.41(s, 3H), 1.45(d, J = 5.6 Hz,1H), 2.12(d, J = 6.0 Hz,1H),3.27(s, 3H), 4.36(s, 2H), 7.12-7.27(m, 5H), 7.73(s, 1H), 8.53(s,1H),9.49(brs, 1H), 12.24(brs,1H) 2-520

(DMSO-d6-400)1.18-1.27(m, 4H), 1.83-1.95(m,1H), 5.28(s, 2H),7.18-7.04(m,5H), 7.51(s, 1H), 7.73(s, 1H),7.99(s, 1H), 8.48(s, 1H) 2-521

(CDCl3-300)1.34(d, J = 6.7 Hz, 3H), 1.37(t,J = 7.1 Hz, 3H), 2.36(dq, J =10.6,6.7 Hz, 1H), 3.08(d, J = 10.6 Hz,1H), 4.34(q, J = 7.1 Hz,2H),6.11(brs, 1H), 7.01(d, J = 4.0 Hz,1H), 7.12-7.31(m, 5H), 7.52(d,J =4.0 Hz, 1H), 8.04(s, 1H),8.33(s, 1H) 2-522

(DMSO-d6-300)1.27(d, J = 6.2 Hz, 3H), 2.01(dq,J = 10.3, 6.2 Hz, 1H),2.79(d,J = 10.3 Hz, 1H), 7.13-7.31(m, 5H),7.51(d, J = 4.0 Hz, 1H),7.55(d,J = 4.0 Hz, 1H), 8.09(s, 1H),9.06(brs, 1H), 9.12(s, 1H) 2-523

(CDCl3-300)1.37(d, J = 7.0 Hz, 3H), 1.56(s,3H), 1.58(s, 3H), 2.45(dq,J =10.6, 7.0 Hz, 1H), 3.06(d,J = 10.6 Hz, 1H), 6.16(s, 1H),6.85(d, J = 4.0Hz, 1H), 7.09-7.30(m, 5H), 7.446(d, J = 4.0 Hz,1H), 7.59(s, 1H), 7.78(s,1H) 2-524

(MeOH-d4-300)1.36(d, J = 6.0 Hz, 3H), 2.12-2.22(m, 1H), 2.91(d, J = 9.0Hz,1H), 3.21(s, 3H), 7.14-7.28(m,5H), 7.35(d, J = 3.0 Hz, 1H),7.53(d, J= 3.0 Hz, 1H), 8.07(s,1H), 8.91(s, 1H) 2-525

(DMSO-d6-300)1.26(d, J = 6.8 Hz, 3H), 1.98(dq,J = 10.5, 6.8 Hz, 1H),2.78(d,J = 10.5 Hz, 1H), 4.55(s, 2H),5.28(brs, 1H), 7.14-7.45(m,7H),7.48-7.65(m, 2H), 7.50(d,J = 3.8 Hz, 1H), 7.55(d, J = 3.8 Hz,1H),9.00(brs, 1H), 12.29(brs,1H) 2-526

(DMSO-d6-300)1.40(s, 3H), 1.42(d, J = 5.7 Hz,1H), 2.12(d, J = 5.7 Hz,1H), 7.12-7.28(m, 5H), 7.67(d, J = 4.1 Hz,1H), 8.01(d, J = 4.1 Hz,1H),8.06(d, J = 6.8 Hz, 2H), 8.78(d,J = 6.8 Hz, 2H), 9.39(s, 1H) 2-527

(DMSO-d6-300)1.35-1.46(m, 4H), 2.10(d,J = 6.0 Hz, 1H), 7.11-7.28(m,5H),7.56-7.63(m, 2H), 7.71(d,J = 3.8 Hz, 1H), 8.24(dt, J = 8.0,1.9 Hz,1H), 8.64(dd, J = 4.9,1.9 Hz, 1H), 9.02(d, J = 1.9 Hz, 1H),9.25(s, 1H)2-528

(CDCl3-300)1.30(d, J = 6.8 Hz, 3H), 2.13-2.26(m, 1H), 2.84(t, J = 5.8Hz,2H), 3.13(d, J = 10.5 Hz, 1H),3.53(t, J = 5.8 Hz, 2H), 3.82(s,3H),3.84(s, 3H), 4.36(s, 2H),5.62(s, 1H), 6.53(s, 3H), 6.59(s,3H),7.15-7.28(m, 5H) 2-529

(DMSO-d6-300)1.26(d, J = 6.8 Hz, 3H), 1.95-2.06(m, 1H), 2.84(d, J = 10.5Hz,1H), 2.98-3.07(m, 4H), 3.34-3.46(m, 4H), 4.23(d, J = 5.7 Hz,2H),7.09-7.36(m, 11H), 8.25(s,1H), 12.32(s, 1H) 2-530

(DMSO-d6-300)0.86(d, J = 6.0 Hz, 6H), 1.20-1.35(m, 5H), 1.48-1.62(m,1H),1.92-2.06(m, 1H), 2.22-2.31(m,2H), 2.33-2.44(m, 4H), 2.85(d,J = 10.5Hz, 1H), 2.99-3.08(m, 4H),7.11-7.32(m, 5H), 8.14(s, 1H) 2-531

(DMSO-d6-300)1.26(d, J = 6.8 Hz, 3H), 1.93-2.05(m, 1H), 2.41-2.56(m,6H),2.72(t, J = 7.5 Hz, 2H), 2.86(d,J = 10.2 Hz, 1H), 2.98-3.12(m,4H),7.09-7.33(m, 11H), 8.16(s, 1H) 2-532

(DMSO-d6-300)1.26(d, J = 7.2 Hz, 3H), 1.94-2..06(m, 1H), 2.84(d, J =10.9 Hz,1H), 3.01-3.10(m, 4H), 3.39-3.51(m, 4H), 5.09(s, 2H),7.15-7.42(m, 10H), 8.28(s, 1H),12.30(s, 1H) 2-533

(DMSO-d6-300)1.27(d, J = 6.8 Hz, 3H), 1.96-2.09(m, 1H), 2.87(d, J = 10.2Hz,1H), 3.13-3.26(m, 4H), 3.73-3.81(m, 4H), 7.15-7.31(m, 7H),8.28(d, J =7.5 Hz, 2H), 8.42(s,1H), 12.37(s, 1H) 2-534

(DMSO-d6-300)1.28(d, J = 6.2 Hz, 3H), 1.95-2.07(m, 1H), 2.86(d, J = 10.6Hz,1H), 2.98-3.73(m, 15H), 7.12-7.31(m, 5H), 8.50(s, 1H),10.26(s, 1H),12.39(s, 1H) 2-535

(DMSO-d6-300)1.25(d, J = 7.0 Hz, 3H), 1.95-2.08(m, 1H), 2.87(t, J = 6.1Hz,2H), 3.40(t, J = 6.1 Hz, 2H),4.30(s, 2H), 7.11-7.29(m, 9H),8.32(s,1H), 12.32(s, 1H) 2-536

(DMSO-d6-300)1.25(d, J = 6.8 Hz, 3H), 1.96(dq,J = 6.8, 10.2 Hz, 1H),2.34-2.42(m,4H), 2.83(d, J = 10.2 Hz, 1H), 3.01-3.10(m, 4H), 3.40(s,2H), 3.73(s,3H), 6.87(d, J = 9.0 Hz, 2H), 7.14-7.29(m, 5H), 7.19(d, J =9.0 Hz,2H), 8.13(brs, 1H) 2-537

(DMSO-d6-300)1.25(d, J = 6.8 Hz, 3H), 1.97(dq,J = 6.8, 10.5 Hz, 1H),2.41-2.54(m,4H), 2.85(d, J = 10.5 Hz, 1H), 3.02-3.15(m, 6H),6.22-6.32(m, 1H),6.54(d, J = 16.2 Hz, 1H), 7.14-7.36(m, 8H),7.39-7.46(m, 2H),8.16(brs, 1H) 2-538

(CD2Cl2-400)1.18-1.20(m, 3H), 1.96-2.00(m,1H), 2.92(d, J = 10.4 Hz,1H),4.53(s, 4H), 7.05-7.24(m, 8H) 2-539

(MeOH-d4-400)1.74-1.81(m, 1H), 3.06(d,J = 12.3 Hz, 1H), 3.37(s, 3H),3.77-3.91(m, 2H), 7.15-7.30(m, 5H),7.63-7.73(m, 3H) 2-540

(DMSO-d6-300)1.26(d, J = 6.8 Hz, 3H), 1.98(dq,J = 10.2, 6.8 Hz, 1H),2.31-2.47(m,2H), 2.78(d, J = 10.2 Hz, 1H), 3.46-3.72(m, 6H),7.14-7.31(m, 6H),7.32-7.49(m, 1H), 7.50-7.71(m,2H), 7.52(d, J = 3.8 Hz,1H),7.56(d, J = 3.8 Hz, 1H), 9.03(s,1H), 12.30(brs, 1H) 2-541

(DMSO-d6-300)1.21(d, J = 6.4 Hz, 3H), 1.82(dq,J = 10.5, 6.4 Hz, 1H),2.64(d,J = 10.5 Hz, 1H), 2.91(t, J = 7.5 Hz,2H), 3.13(t, J = 7.5 Hz,2H),6.84(d, J = 3.4 Hz, 1H), 7.07-7.30(m, 10H), 7.36(d, J = 3.4 Hz,1H)2-542

(MeOH-d4-400)1.38(d, J = 6.5 Hz, 3H), 2.19-2.23(m, 1H), 2.95(d, J = 10.2Hz,1H), 6.54(t, J = 2.1 Hz, 1H), 7.16-7.30(m, 6H), 7.51(d, J = 4.2Hz,1H), 7.70(d, J = 2.1 Hz, 1H),8.23(d, J = 2.1 Hz, 1H) 2-543

(DMSO-d6-300)1.26(d, J = 6.6 Hz, 3H), 1.91-2.06(m, 1H), 2.78(d, J = 10.6Hz,1H), 7.14-7.30(m, 5H), 7.35(d,J = 4.0 Hz, 1H), 7.48(d, J = 4.0Hz,1H), 7.87(s, 1H), 8.79(s, 1H),9.03(brs, 1H), 12.27(brs, 1H) 2-544

(DMSO-d6-300)1.37-1.42(m, 4H), 2.09(d,J = 5.7 Hz, 1H), 7.11-7.27(m,5H),7.49(d, J = 8.3 Hz, 1H), 7.52-7.59(m, 3H), 7.88(d, J = 1.5 Hz,1H),9.19(brs, 1H), 12.12(brs,1H) 2-545

(MeOH-d4-300)1.37(d, J = 6.6 Hz, 3H), 2.21(dq,J = 10.6, 6.6 Hz, 1H),2.95(d,J = 10.6 Hz, 1H), 5.40(d, J = 2.2 Hz,1H), 5.84(d, J = 2.2 Hz,1H), 7.11-7.30(m, 6H), 7.50(d, J = 4.0 Hz,1H), 7.92(s, 1H), 8.44(s, 1H)2-546

(DMSO-d6-300)1.27(d, J = 6.8 Hz, 3H), 2.01(dq,J = 10.2, 6.8 Hz, 1H),2.46(s, 3H),2.79(d, J = 10.2 Hz, 1H), 7.14-7.31(m, 5H), 7.51(d, J = 4.1Hz,1H), 7.54(d, J = 4.1 Hz, 1H),8.21(s, 1H), 9.10(brs, 1H),9.27(s, 1H),12.30(brs, 1H) 2-547

(DMSO-d6-300)1.26(d, J = 6.4 Hz, 3H), 1.37(d,J = 6.4 Hz, 3H), 1.99(dq, J= 10.5 Hz,6.4 Hz, 1H), 2.78(d, J = 10.5 Hz,1H), 4.74(dq, J = 4.9, 6.4Hz, 1H),5.14(d, J = 4.9 Hz, 1H), 7.14-7.28(m, 5H), 7.30(d, J = 4.1Hz,1H), 7.46(d, J = 4.1 Hz, 1H),7.68(s, 1H), 8.38(s, 1H),8.99(brs, 1H),12.27(brs, 1H) 2-548

(MeOH-d4-400)1.29(s, 3H), 2.15(m, 1H), 2.93-2.96(d, J = 10.8 Hz, 1H),4.55-4.63(m, 4H), 6.67-7.28(m, 8H) 2-549

(MeOH-d4-400)1.29(t, J = 6.4 Hz, 3H), 2.03-2.13(m, 3H), 2.99(t, J = 9.7Hz,1H), 3.40-3.50(m, 4H), 4.17-4.24(m, 1H), 4.41-4.50(m,2H),7.16-7.33(m, 9H) 2-550

(MeOH-d4-400)1.30(t, J = 7.04 Hz, 3H), 2.04-2.13(m, 3H), 2.99(dd, J =10.5,13.1 Hz, 1H), 3.41-3.48(m, 4H),4.19-4.22(m, 1H), 4.41-4.51(m,2H),7.15-7.37(m, 9H) 2-551

(MeOH-d4-400)1.29(t, J = 6.44 Hz, 3H), 2.06-2.16(m, 3H), 3.00(dd, J =10.5,12.9 Hz, 1H), 3.43-3.56(m, 4H),4.26-4.30(m, 1H), 4.44-4.58(m,2H),7.13-7.52(m, 8H) 2-552

(MeOH-d4-400)1.19-1.38(m, 9H), 2.18-2.22(m,1H), 3.00(d, J = 10.5 Hz,1H), 3.70-3.76(m, 1H), 4.72-4.85(m, 4H),7.16-7.44(m, 8H) 2-553

(MeOH-d4-400)1.29(t, J = 6.3 Hz, 3H), 2.06-2.17(m, 3H), 3.00(dd, J =4.9,10.4 Hz, 1H), 3.39-3.54(m, 4H),4.24-4.28(m, 1H), 4.45-4.58(m,2H),7.16-7.47(m, 8H) 2-554

(DMSO-d6-400)1.65(dd, J = 10.0, 5.8 Hz, 1H),2.02(dd, J = 8.6, 5.8 Hz,1H),2.79(t, J = 9.3 Hz, 1H), 7.14-7.26(m, 5H), 8.03-8.07(m, 2H),8.32(dd,J = 8.8, 2.3 Hz, 1H),8.77(d, J = 2.3 Hz, 1H), 8.88(d,J = 1.4 Hz, 1H),9.23(s, 1H),12.13(brs, 1H) 2-555

(DMSO-d6-300)1.27(d, J = 6.8 Hz, 3H), 1.35(t,J = 7.2 Hz, 3H), 2.01(dd, J= 10.5,6.8 Hz, 1H), 2.80(d, J = 10.5 Hz,1H), 4.41(q, J = 7.0 Hz, 2H),7.16-7.30(m, 5H), 7.66(d, J = 3.8 Hz,1H), 7.87(d, J = 4.1 Hz,1H),7.99(s, 1H), 9.22(s, 1H),12.32(brs, 1H) 2-556

(DMSO-d6-300)1.27(d, J = 6.4 Hz, 3H), 2.05(dq,J = 10.5, 6.4 Hz, 1H),2.83(d,J = 10.5 Hz, 1H), 7.13-7.32(m, 5H),8.17(d, J = 8.7 Hz, 1H),8.39(s,1H), 8.39(dd, J = 8.7, 1.9 Hz, 1H),8.85(d, J = 1.9 Hz, 1H),9.17(s,1H), 9.30(s, 1H), 12.24(s, 1H) 2-557

(DMSO-d6-400)1.25(d, J = 7.0 Hz, 3H), 2.02(dq,J = 10.2, 7.0 Hz, 1H),2.80(d,J = 10.2 Hz, 1H), 7.13-7.28(m, 5H),8.05(s, 1H), 8.07(d, J = 8.8Hz,1H), 8.32(dd, J = 8.8, 2.3 Hz, 1H),8.78(d, J = 2.3 Hz, 1H),8.89(s,1H), 9.11(s, 1H), 12.24(brs, 1H) 2-558

(DMSO-d6-400)1.65(dd, J = 9.3, 5.8 Hz, 1H),2.02(dd, J = 9.3, 5.8 Hz,1H),2.79(t, J = 9.3 Hz, 1H), 7.13-7.27(m, 5H), 8.13(d, J = 8.8 Hz,1H),8.37(dd, J = 8.8, 2.3 Hz, 1H),8.37(s, 1H), 8.81(d, J = 2.3 Hz,1H),9.27(s, 2H), 12.11(brs, 1H) 2-559

(MeOH-d4-300)1.32-1.46(m, 2H), 1.68-1.85(m,1H), 1.73(d, J = 6.0 Hz, 1H),1.91-2.06(m, 1H), 2.18(d, J = 6.0 Hz,1H), 3.19(s, 3H), 3.21-3.34(m,2H),7.09-7.26(m, 5H), 7.37(d,J = 3.0 Hz, 1H), 7.43(d, J = 9.0 Hz,2H),7.55(d, J = 3.0 Hz, 1H),7.65(d, J = 9.0 Hz, 2H) 2-560

(MeOH-d4-300)1.37-1.42(m, 2H), 1.73(d,J = 5.9 Hz, 1H), 1.74-1.80(m,1H),1.96-1.98(m, 1H), 2.17(d,J = 5.9 Hz, 1H), 3.20(s, 3H), 7.14-7.19(m,6H), 7.45(d, J = 4.0 Hz,1H), 7.66(s, 1H), 8.38(s, 1H) 2-561

(MeOH-d4-300)1.36(d, J = 7.0 Hz, 3H), 2.17-2.20(m, 1H), 2.92(d, J = 10.3Hz,1H), 4.55(s, 2H), 7.12(d,J = 4.0 Hz, 1H), 7.23-7.24(m, 5H),7.49(d, J= 4.4 Hz, 1H), 7.66(s,1H), 8.15(s, 1H) 2-562

(DMSO-d6-300)1.37(d, J = 7.5 Hz, 1H), 1.38(s,3H), 2.08(d, J = 5.3 Hz,1H), 6.69-6.77(m, 1H), 7.16-7.23(m, 6H),7.50-7.53(m, 2H), 9.27(brs,1H),12.11(brs, 1H) 2-563

(DMSO-d6-300)1.34(d, J = 5.7 Hz, 1H), 1.38(s,3H), 2.09(d, J = 5.7 Hz,1H), 6.10-6.14(m, 1H), 7.13-7.31(m, 6H),7.39(d, J = 4.1 Hz, 1H),7.54(d,J = 3.8 Hz, 1H), 9.30(brs, 1H),12.12(brs, 1H) 2-564

(DMSO-d6-300)1.37-1.43(m, 1H), 1.40(s, 3H),2.10(d, J = 5.3 Hz, 1H),4.59(d,J = 5.3 Hz, 2H), 5.53(t, J = 5.3 Hz,1H), 7.13-7.27(m, 5H),7.49(d,J = 8.3 Hz, 1H), 7.53-7.55(m, 2H),7.65(dd, J = 8.3, 2.3 Hz,1H),7.81(d, J = 2.3 Hz, 1H), 9.19(s,1H), 12.09(s, 1H) 2-565

(DMSO-d6-300)1.26(d, J = 6.8 Hz, 3H), 1.99(dq,J = 10.2, 6.8 Hz, 1H),2.78(d,J = 10.2 Hz, 1H), 4.59(d, J = 5.3 Hz,2H), 5.52(t, J = 5.3 Hz,1H), 7.17-7.30(m, 5H), 7.49(d, J = 8.3 Hz,1H), 7.53(d, J = 3.8 Hz,1H),7.56(d, J = 3.8 Hz, 1H), 7.64(dd,J = 8.3, 2.3 Hz, 1H), 7.81(d,J =2.3 Hz, 1H), 9.04(s, 1H),12.30(s, 1H) 2-566

(CDCl3-300)1.55(s, 4H), 1.98(d, J = 5.7 Hz,1H), 2.24(d, J = 5.7 Hz,1H),5.87(s, 1H), 7.07-7.13(m, 2H),7.16-7.35(m, 5H), 7.39-7.45(m,1H),7.49-7.58(m, 2H) 2-567

(CDCl3-300)1.56(s, 3H), 1.98(d, J = 6.0 Hz,1H), 2.26(d, J = 6.0 Hz,1H),5.90(s, 1H), 7.07-7.14(m, 2H),7.19-7.28(m, 3H), 7.30-7.36(m,1H),7.58-7.63(m, 1H), 7.65-7.74(m, 4H) 2-568

(DMSO-d6-300)1.28(d, J = 5.3 Hz, 1H), 1.35(s,3H), 2.03(d, J = 5.3 Hz,1H),4.04(s, 2H), 7.08-7.26(m, 5H),7.50(dd, J = 8.1, 2.1 Hz, 1H),7.73(d,J = 2.1 Hz, 1H), 7.80(dd,J = 8.1, 2.1 Hz, 1H), 7.98(d,J = 2.1 Hz, 1H),8.03(d, J = 8.1 Hz,1H), 8.09(d, J = 8.1 Hz, 1H),8.87(s, 1H) 2-569

(DMSO-d6-300)1.22(d, J = 6.4 Hz, 3H), 1.88(d,J = 38.4 Hz, 1H), 2.66(d, J= 10.9 Hz,1H), 4.04(s, 2H), 7.13-7.28(m,5H), 7.50(dd, J = 8.3, 1.9 Hz,1H),7.72(d, J = 1.9 Hz, 1H), 7.84(dd,J = 8.3, 1.9 Hz, 1H), 8.00(d,J =1.9 Hz, 1H), 8.02(d, J = 8.3 Hz,1H), 8.09(d, J = 8.3 Hz, 1H),8.72(s, 1H)2-570

(DMSO-d6-300)1.27(d, J = 6.4 Hz, 3H), 1.99(dd,J = 10.5, 6.0 Hz, 1H),2.79(d,J = 9.8 Hz, 1H), 7.02(t, J = 7.0 Hz,1H), 7.16-7.31(m, 5H),7.39(t,J = 7.9 Hz, 1H), 7.56(q, J = 3.9 Hz,2H), 7.64(d, J = 9.4 Hz,1H),8.50(s, 1H), 8.58(d, J = 7.2 Hz,1H), m9.02(s, 1H), 12.24(brs, 1H)2-571

(DMSO-d6-300)1.27(d, J = 6.8 Hz, 3H), 2.00(dd,J = 9.8, 6.8 Hz, 1H),2.79(d,J = 10.2 Hz, 1H), 3.59(brs, 2H),7.11(t, J = 5.5 Hz, 1H),7.16-7.30(m, 4H), 7.59(dd, J = 9.4,3.8 Hz, 2H), 8.42(s, 1H),8.53-8.60(m, 1H), 8.93-9.03(m, 2H),12.25(brs, 1H) 2-572

(DMSO-d6-300)1.39-1.42(m, 1H), 1.40(s, 3H),2.10(d, J = 5.7 Hz, 1H),7.11-7.28(m, 5H), 7.59(d, J = 3.8 Hz,1H), 7.70(d, J = 3.8 Hz,1H),7.81(d, J = 8.3 Hz, 2H), 7.95(d,J = 8.3 Hz, 2H), 9.24(brs,1H),12.12(brs, 1H) 2-573

(DMSO-d6-300)1.39-1.42(m, 1H), 1.40(s, 3H),2.10(d, J = 5.3 Hz, 1H),2.60(s,3H), 7.10-7.28(m, 5H), 7.58(d,J = 4.1 Hz, 1H), 7.70(d, J = 4.1Hz,1H), 7.87(d, J = 8.3 Hz, 2H),8.02(d, J = 8.3 Hz, 2H), 9.23(brs,1H),12.11(brs, 1H) 2-574

(DMSO-d6-300)1.38-1.42(m, 1H), 1.39(s, 3H),2.08(d, J = 4.1 Hz, 1H),4.53(s,2H), 7.10-7.27(m, 5H), 7.39(d,J = 8.3 Hz, 2H), 7.50(d, J = 3.8Hz,1H), 7.53(d, J = 3.8 Hz, 1H),7.67(d, J = 8.3 Hz, 2H), 9.14(brs,1H),12.09(brs, 1H) 2-575

(DMSO-d6-300)1.37-1.44(m, 1H), 1.40(s, 3H),2.09(d, J = 5.7 Hz, 1H),3.73(dt,J = 4.9, 5.5 Hz, 2H), 4.06(t,J = 4.9 Hz, 2H), 4.86(t, J = 5.5Hz,1H), 6.96-7.02(m, 1H), 7.13-7.29(m, 7H), 7.33-7.40(m, 1H),7.53(d, J =3.8 Hz, 1H), 7.56(d,J = 3.8 Hz, 1H), 9.16(s, 1H),12.10(s, 1H) 2-576

(DMSO-d6-300)1.37-1.43(m, 1H), 1.39(s, 3H),1.88(tt, J = 6.2, 6.4 Hz,2H),2.09(d, J = 5.7 Hz, 1H), 3.53-3.60(m, 2H), 4.10(t, J = 6.4 Hz,2H),4.54(brs, 1H), 6.95-7.01(m,1H), 7.11-7.28(m, 7H), 7.32-7.39(m, 1H),7.53(d, J = 3.8 Hz,1H), 7.56(d, J = 3.8 Hz, 1H),9.15(s, 1H), 12.10(s,1H) 2-577

(DMSO-d6-300)1.27(d, J = 6.8 Hz, 3H), 2.01(dq,J = 10.2, 6.8 Hz, 1H),2.80(d,J = 10.2 Hz, 1H), 7.14-7.32(m, 5H),7.50(d, J = 4.1 Hz, 1H),7.54(d,J = 4.1 Hz, 1H), 8.27(s, 1H),9.11(brs, 1H), 9.29(s,1H),12.26(brs, 1H) 2-578

(MeOH-d4-300)1.39(d, J = 6.8 Hz, 3H), 2.23(dq,J = 10.5, 6.8 Hz, 1H),2.97(d,J = 10.5 Hz, 1H), 7.18-7.30(m, 5H),7.40(s, 1H), 7.62-7.68(m, 2H)2-579

(CDCl3-300)1.33(d, J = 6.8 Hz, 3H), 2.22-2.33(m, 1H), 3.03(d, J = 10.9Hz,1H), 7.13-7.30(m, 6H), 7.44(d,J = 3.8 Hz, 1H), 7.65(d, J = 3.8 Hz,1H)2-580

(CDCl3-300)1.33(d, J = 6.0 Hz, 3H), 2.27-2.39(m, 1H), 3.06(d, J = 12.0Hz,1H), 5.98(brs, 1H), 7.09(d,J = 6.0 Hz, 1H), 7.11-7.29(m, 5H),7.55(d,J = 6.0 Hz, 1H), 7.96(s,1H), 8.30(s, 1H) 2-581

(DMSO-d6-300)1.35-1.43(m, 4H), 2.09(d,J = 5.3 Hz, 1H), 7.11(s, 5H),7.11-7.29(m, 5H), 7.46-7.62(m, 2H),7.55(d, J = 3.8 Hz, 1H), 7.59(d,J =3.8 Hz, 1H), 7.84-7.95(m, 1H),9.20(s, 1H), 12.10(brs, 1H) 2-582

(DMSO-d6-300)1.35-1.42(m, 1H), 1.39(s, 3H),2.06(d, J = 6.0 Hz, 1H),6.83(d,J = 8.7 Hz, 2H), 7.10-7.27(m, 5H),7.32(d, J = 3.8 Hz, 1H),7.47(d,J = 3.8 Hz, 1H), 7.53(d, J = 8.7 Hz,2H), 9.07(brs, 1H),9.84(brs,1H), 12.08(brs, 1H) 2-583

(DMSO-d6-300)1.37-1.46(m, 1H), 1.41(s, 3H),2.09(d, J = 5.7 Hz, 1H),5.16(brs,2H), 6.63(dd, J = 8.3, 7.2 Hz, 1H),6.81(d, J = 8.3 Hz, 1H),7.06-7.27(m, 8H), 7.51(d, J = 4.1 Hz,1H), 9.08(brs, 1H) 2-584

(DMSO-d6-300)1.27(d, J = 6.8 Hz, 3H), 2.01(dq,J = 10.5, 6.8 Hz, 1H),2.80(d,J = 10.5 Hz, 1H), 7.15-7.31(m, 7H),7.53(d, J = 7.2 Hz, 1H),7.61-7.68(m, 1H), 7.64(d, J = 3.8 Hz,1H), 7.77(d, J = 3.8 Hz,1H),9.12(brs, 1H), 12.30(brs, 1H)13.20(brs, 1H) 2-585

(DMSO-d6-300)0.99(d, J = 5.3 Hz, 1H), 1.16(s,3H), 1.99(d, J = 5.7 Hz,1H), 7.13-7.21(m, 5H), 7.42(t, J = 7.3 Hz,1H), 7.54(t, J = 7.5 Hz, 2H),7.80-7.82(m, 3H), 8.18(d, J = 8.7 Hz,1H), 8.47(d, J = 1.9 Hz,1H),8.51(s, 1H), 9.44(brs, 1H),12.07(brs, 1H) 2-586

(DMSO-d6-300)1.41(s, 3H), 1.42(d, J = 7.5 Hz,1H), 2.12(d, J = 5.7 Hz,1H),4.15(s, 3H), 7.13-7.27(m, 5H),7.54(d, J = 4.1 Hz, 1H), 7.63(d,J =3.8 Hz, 1H), 8.11(s, 1H),9.31(brs, 1H), 12.09(brs, 1H) 2-587

(DMSO-d6-300)1.38(d, J = 4.1 Hz, 1H), 1.39(s,3H), 2.09(d, J = 5.7 Hz,1H),4.10(s, 3H), 7.12-7.26(m, 5H),7.41(d, J = 4.1 Hz, 1H), 7.54(d,J =3.8 Hz, 1H), 8.59(s, 1H),9.16(brs, 1H) 2-588

(CDCl3-300)1.30-1.50(m, 2H), 1.69(d,J = 6.0 Hz, 1H), 1.82(t, J = 7.5Hz,2H), 2.08(d, J = 6.0 Hz, 1H), 3.20-3.34(m, 2H), 3.24(s, 3H),6.73(brs,1H), 6.99-7.10(m, 3H),7.14-7.22(m, 3H), 7.46(d,J = 6.0 Hz, 1H), 7.60(d,J = 6.0 Hz,1H) 2-589

(CDCl3-300)1.55(s, 3H), 1.98(d, J = 6.0 Hz,1H), 2.24(d, J = 6.0 Hz,1H),5.84(s, 1H), 7.00-7.13(m, 4H),7.17-7.35(m, 5H), 7.53(d,J = 4.1 Hz,1H) 2-590

(CDCl3-300)1.33(d, J = 7.2 Hz, 3H), 2.26-2.40(m, 1H), 3.09(d, J = 10.9Hz,1H), 5.82(s, 1H), 7.14-7.31(m,6H), 7.62(d, J = 4.1 Hz, 1H),7.67-7.70(m, 4H) 2-591

(CDCl3-300)1.37(d, J = 6.4 Hz, 3H), 2.32-2.45(m, 1H), 3.11(d, J = 10.5Hz,1H), 6.19(s, 1H), 7.22(d,J = 59.5 Hz, 4H), 7.39-7.54(m, 4H),7.60(d, J= 4.1 Hz, 1H), 7.86(d,J = 8.3 Hz, 1H), 8.00(d, J = 8.3 Hz,1H) 2-592

(CDCl3-300)1.38(s, 3H), 1.99(d, J = 6.4 Hz,2H), 2.03(d, J = 6.4 Hz,2H),3.88(s, 3H), 4.78(d, J = 13.6 Hz,1H), 4.91(d, J = 13.6 Hz, 1H),6.63-6.70(m, 3H), 6.92-6.98(m, 2H),7.02-7.13(m, 3H), 7.40(d,J = 3.8 Hz,1H), 7.54(dd, J = 8.3,2.3 Hz, 1H), 7.73(d, J = 2.3 Hz, 1H) 2-593

(CDCl3-300)1.50(s, 3H), 1.80(d, J = 6.0 Hz,1H), 2.16(d, J = 6.0 Hz,1H),5.95(s, 1H), 7.01-7.08(m, 2H),7.18-7.24(m, 3H), 7.35(d,J = 4.1 Hz,1H), 7.43-7.51(m, 2H),7.58(d, J = 4.1 Hz, 1H), 7.68(dd,J = 8.5, 6.6 Hz,1H) 2-594

(CDCl3-300)1.53(s, 3H), 1.97(d, J = 6.0 Hz,1H), 2.19(d, J = 6.0 Hz,1H),4.77(s, 2H), 5.79(s, 1H), 7.02-7.09(m, 2H), 7.15-7.30(m,5H),7.37(dd, J = 8.1, 1.7 Hz, 1H),7.48(d, J = 7.5 Hz, 1H), 7.51(d,J =4.1 Hz, 1H) 2-595

(DMSO-d6-300)1.36-1.43(m, 4H), 2.08(d,J = 5.7 Hz, 1H), 3.90(s, 3H),7.10-7.27(m, 6H), 7.48-7.52(m, 2H),7.65(dd, J = 8.7, 2.3 Hz, 1H),7.82(d,J = 2.3 Hz, 1H), 9.15(brs,1H), 12.09(brs, 1H) 2-596

(DMSO-d6-400)1.21(d, J = 6.7 Hz, 3H), 1.84(dq,J = 10.2, 6.7 Hz, 3H),2.62(d,J = 10.2 Hz, 1H), 7.12-7.27(m, 5H),7.48-7.81(m, 5H), 8.01(brs,1H),8.18(d, J = 6.5 Hz, 2H), 8.64(s,1H), 12.10(s, 1H), 13.30(s, 1H)2-597

(DMSO-d6-300)1.30(s, 3H), 1.45(d, J = 6.8 Hz,3H), 2.32(q, J = 6.8 Hz,1H), 7.18-7.32(m, 5H), 7.34(d, J = 3.8 Hz,1H), 7.78(d, J = 3.8 Hz,1H),8.15(s, 1H), 8.49(brs, 1H),12.50(brs, 1H) 2-598

(DMSO-d6-300)1.15(d, J = 6.8 Hz, 3H), 1.30(s,3H), 2.39(q, J = 6.8 Hz,1H), 7.13-7.27(m, 5H), 7.68(d, J = 4.1 Hz,1H), 7.83(d, J = 4.1 Hz,1H),8.16(s, 1H), 8.96(s, 1H),12.08(brs, 1H) 2-599

(DMSO-d6-300)1.40(s, 3H), 1.43(d, J = 5.5 Hz,1H), 2.10(d, J = 5.5 Hz,1H), 7.11-7.28(m, 5H), 7.51(d, J = 4.0 Hz,1H), 7.53(d, J = 4.0 Hz,1H),8.26(s, 1H), 9.24(brs, 1H),9.30(s, 1H), 12.09(brs, 1H) 2-600

(DMSO-d6-300)1.36-1.44(m, 1H), 1.38(s, 3H),2.01-2.09(m, 1H),7.08-7.26(m,8H), 7.38(d, J = 3.8 Hz, 1H),7.50(d, J = 3.8 Hz, 1H) 2-601

(DMSO-d6-300)1.37-1.43(m, 1H), 1.39(s, 3H),2.08(d, J = 5.3 Hz, 1H),7.03-7.08(m, 1H), 7.13-7.27(m, 6H),7.444-7.48(m, 1H), 7.51(d,J = 3.8 Hz,1H) 2-602

(CDCl3-300)1.51(s, 3H), 1.85(d, J = 6.0 Hz,1H), 2.21(d, J = 6.0 Hz,1H),3.17(s, 3H), 6.24(brs, 1H), 6.99-7.11(m, 3H), 7.15-7.23(m,3H),7.50(d, J = 6.0 Hz, 1H), 8.00(s1H), 8.42(s, 1H) 2-603

(CDCl3-300)1.59(s, 3H), 2.04(d, J = 6.0 Hz,1H), 2.25(d, J = 6.0 Hz,1H),4.62(s, 2H), 6.04(brs, 1H),6.84(d, J = 6.0 Hz, 1H), 7.09-7.28(m,5H), 7.43(d, J = 6.0 Hz,1H), 7.63(s, 1H), 7.77(s, 1H) 2-604

(DMSO-d6-300)1.27(d, J = 6.8 Hz, 3H), 2.02(dq,J = 10.5, 6.8 Hz, 1H),2.79(d,J = 10.5 Hz, 1H), 7.14-7.31(m, 7H),7.54-7.71(m, 1H), 7.65(d,J =3.8 Hz, 1H), 7.80(d, J = 3.8 Hz,1H) 2-605

(MeOH-d4-300)2.08(dd, J = 9.4, 5.7 Hz, 1H),2.30(dd, J = 8.3, 5.7 Hz,1H),2.75(dd, J = 9.4, 8.3 Hz, 1H), 7.18-7.30(m, 6H), 7.41(d, J = 4.1Hz,1H), 7.72(s, 1H), 8.45(s, 1H) 2-606

(DMSO-d6-300)1.40(s, 3H), 1.41(d, J = 5.7 Hz,1H), 2.10(d, J = 5.7 Hz,1H),3.92(td, J = 13.9, 6.2 Hz, 2H),5.64(t, J = 6.2 Hz, 1H), 7.11-7.27(m,5H), 7.52-7.65(m, 4H),7.78-7.88(m, 2H), 9.20(brs, 1H),12.10(brs, 1H)2-607

(DMSO-d6-300)1.28(d, J = 6.8 Hz, 3H), 2.01(dq,J = 10.2, 6.8 Hz, 1H),2.80(d,J = 10.2 Hz, 1H), 3.81(s, 3H),6.87(d, J = 8.7 Hz, 1H),7.07(s,1H), 7.15-7.32(m, 5H), 7.49(d,J = 8.7 Hz, 1H), 7.62(d, J = 3.8Hz,1H), 7.71(d, J = 3.8 Hz, 1H),9.12(s, 1H), 12.30(brs, 1H) 2-608

(DMSO-d6-300)1.39(s, 3H), 1.45(d, J = 5.5 Hz,1H), 2.11(d, J = 5.5 Hz,1H),7.19(d, J = 8.4 Hz, 2H), 7.30(d,J = 8.4 Hz, 2H), 7.68(d, J = 4.0Hz,1H), 7.85(d, J = 4.0 Hz, 1H),8.15(s, 1H) 2-609

(DMSO-d6-300)1.16(d, J = 6.6 Hz, 3H), 1.91(dd,J = 10.6, 6.6 Hz, 1H),2.12(t,J = 19.3 Hz, 3H), 2.57(d, J = 10.6 Hz,1H), 7.00-7.10(m, 6H),7.67(d,J = 4.0 Hz, 2H), 7.79(d, J = 4.0 Hz,1H) 2-610

(DMSO-d6-300)1.37(s, 3H), 1.39(d, J = 5.7 Hz,1H), 2.08(d, J = 5.7 Hz,1H),3.67(s, 3H), 6.68-6.77(m, 3H),7.10-7.18(m, 1H), 7.66(d,J = 4.1 Hz,1), 7.84(d, J = 4.1 Hz,1H), 8.15(s, 1H), 9.36(brs, 1H),12.13(brs, 1H)2-611

(DMSO-d6-300)1.40(s, 3H), 1.45(d, J = 5.7 Hz,1H), 2.14(d, J = 5.7 Hz,1H), 6.91-7.06(m, 3H), 7.21-7.35(m, 1H),7.68(d, J = 4.1 Hz, 1H),7.86(d,J = 4.1 Hz, 1H), 8.17(s, 1H),12.26(s, 1H), 12.26(s, 1H) 2-612

(DMSO-d6-300)1.40(s, 3H), 1.45(d, J = 5.7 Hz,1H), 2.13(d, J = 5.7 Hz,1H), 7.10-7.33(m, 4H), 7.69(d, J = 4.1 Hz,1H), 7.86(d, J = 4.1 Hz,1H),8.17(s, 1H), 9.34(s, 1H),12.31(s, 1H) 2-613

(DMSO-d6-300)1.36(s, 3H), 1.59(d, J = 5.5 Hz,1H), 2.02(d, J = 5.5 Hz,1H),3.72(s, 3H), 6.74-6.88(m, 2H),7.05-7.15(m, 2H), 7.63(d,J = 3.7 Hz,1H), 7.76(d, J = 3.7 Hz,1H), 7.89(s, 1H), 8.52(brs, 1H) 2-614

(DMSO-d6-300)1.44(s, 3H), 1.54(d, J = 5.7 Hz,1H), 2.17(d, J = 5.7 Hz,1H),3.13(s, 3H), 7.51-7.56(m, 2H),7.67-7.76(m, 2H), 7.69(d,J = 3.8 Hz,1H), 7.86(d, J = 3.8 Hz,1H), 8.17(s, 1H), 9.43(brs, 1H),12.34(brs, 1H)2-615

(MeOH-d4-300)1.51(s, 3H), 1.89(d, J = 6.0 Hz,1H), 2.18(d, J = 6.0 Hz,1H), 6.96-7.05(m, 2H), 7.17-7.24(m, 2H),7.62-7.67(m, 3H) 2-616

(DMSO-d6-300)1.35(d, J = 16.2 Hz, 3H), 1.66(dd,J = 13.9, 5.3 Hz, 1H),2.05(t,J = 7.0 Hz, 1H), 7.13-7.37(m, 4H),7.68(d, J = 3.0 Hz, 1H),7.84(d,J = 1.5 Hz, 1H), 8.15(s, 1H),9.28(brs, 1H), 12.15(brs, 1H) 2-617

(MeOH-d4-300)1.54(s, 3H), 1.85(d, J = 5.7 Hz,1H), 2.22(d, J = 6.0 Hz,1H),7.29(dd, J = 7.7, 5.1 Hz, 1H), 7.62-7.66(m, 3H), 7.70(dt, J =8.0,1.7 Hz, 1H), 8.30(dd, J = 4.9,1.5 Hz, 1H), 8.41(d, J = 1.9 Hz, 1H)2-618

(DMSO-d6-300)1.40(s, 3H), 1.44(d, J = 5.7 Hz,1H), 2.14(d, J = 5.7 Hz,1H), 6.92-7.05(m, 3H), 7.23-7.34(m, 1H),7.69(d, J = 4.1 Hz, 1H),7.86(d,J = 4.1 Hz, 1H), 8.17(s, 1H),9.38(s, 1H), 12.28(s, 1H) 2-619

(DMSO-d6-300)1.40(s, 3H), 1.45(d, J = 5.7 Hz,1H), 2.13(d, J = 5.7 Hz,1H), 7.10-7.33(m, 4H), 7.69(d, J = 4.1 Hz,1H), 7.86(d, J = 4.1 Hz,1H),8.17(s, 1H), 9.36(s, 1H),12.30(s, 1H) 2-620

(DMSO-d6-300)1.40(s, 3H), 1.44(d, J = 5.7 Hz,1H), 2.13(d, J = 5.7 Hz,1H),7.19(d, J = 8.3 Hz, 2H), 7.32(d,J = 8.7 Hz, 2H), 7.69(d, J = 4.1Hz,1H), 7.86(d, J = 3.8 Hz, 1H),8.17(s, 1H), 9.39(brs, 1H),12.22(brs,1H) 2-621

(DMSO-d6-400)1.38(s, 2H), 1.42(d, J = 5.6 Hz,1H), 2.11(d, J = 5.6 Hz,1H), 7.02-7.10(m, 2H), 7.15-7.23(m, 2H),7.67(d, J = 3.7 Hz, 1H),7.85(d,J = 3.7 Hz, 1H), 8.16(q, J = 0.9 Hz,1H), 9.38(brs, 1H),12.19(brs,1H) 2-622

(DMSO-d6-400)1.23(d, J = 7.0 Hz, 3H), 1.97(dq,J = 10.2, 6.5 Hz, 1H),2.74(d,J = 10.7 Hz, 1H), 7.09-7.27(m, 5H),7.32-7.38(m, 1H),7.43-7.49(m,3H), 7.71(d, J = 9.7 Hz, 1H), 7.93-7.97(m, 2H), 8.58(s, 1H),9.12-9.09(m, 1H) 2-623

(DMSO-d6-400)1.31-1.39(m, 6H), 1.85(q,J = 6.7 Hz, 1H), 7.06-7.29(m,5H),7.67(d, J = 3.8 Hz, 1H), 7.86(d,J = 3.8 Hz, 1H), 8.17(s,1H),9.23(brs, 1H), 12.17(brs, 1H) 2-624

(DMSO-d6-300)1.35-1.37(m, 6H), 1.85(q,J = 6.4 Hz, 1H), 2.13(t, J = 19.3Hz,3H), 7.08-7.28(m, 5H), 7.64(d,J = 4.0 Hz, 1H), 7.71(s, 1H),7.80(d, J= 4.0 Hz, 1H), 9.19(s,1H), 12.17(s, 1H) 2-625

(DMSO-d6-300)1.35-1.37(m, 6H), 1.85(q,J = 6.4 Hz, 1H), 2.13(t, J = 19.3Hz,3H), 7.08-7.28(m, 5H), 7.64(d,J = 4.0 Hz, 1H), 7.71(s, 1H),7.80(d, J= 4.0 Hz, 1H), 9.19(s,1H), 12.17(s, 1H)

The following show the results of experiments performed with regard tothe aggrecanase-1 inhibitory action, matrix metalloproteinase-1 (MMP-1)inhibitory action and matrix metalloproteinase-13 (MMP-13) inhibitoryaction of the compound of the present invention.

(Pharmacological Tests) EXPERIMENTAL EXAMPLE 1

Aggrecanase-1 inhibitory action Particle Assay was used fordetermination of aggrecanase activity.

The enzyme and substrate were diluted with Tris-HCl buffer, and testcompounds were diluted with dimethyl sulfoxide (DMSO).

Test compounds and the enzyme were added into 96-well plate, andpolyacrylamide particles containing aggrecan were added as a substrateand the mixture was incubated at 37° C. for 15 hr.

After incubation, the supernatant was transferred to another plate, andmixed with 1,9-dimethylmethylene blue. The absorbence at 595 nm wasmeasured to quantify the amount of glycosaminoglycan (GAG) released inthe reaction supernatant. Whale chondroitin sulfate was used as thestandard of GAG. The inhibitory activity of the compound in each well(%) was calculated based on the values of enzyme-free well andinhibitor-free well. The inhibitory activity of the compound wasrepresented as IC₅₀ (μM).

EXPERIMENTAL EXAMPLE 2

MMP-1 inhibitory action For MMP-1 Assay, Type I collagen ActivityMeasurement kit (YAGAI YU-72013) modified to a 96-well plate format wasused.

The principle of the kit is based on the property of collagen thatbecomes soluble in ethanol after being cleaved by MMP-1.

The enzyme and substrate were diluted with Tris-HCl buffer, and testcompounds were diluted with dimethyl sulfoxide (DMSO).

The enzyme and test compounds were added into 96-well plate, andfluorescein isothiocianate (FITC)-labeled collagen type I was added as asubstrate and the mixture was incubated at 37° C. for 3 hr.

The reaction was terminated by addition of Tris-HCl buffer containingethanol. After centrifugation, the supernatant containing denaturedsubstrate was transferred to another 96-well plate. The collagenaseactivity of MMP-1 was determined by measuring FITC fluorescenceintensity (excitation wavelength 485 nm, emission wavelength 530 nm) ofeach well. The inhibitory activity of the compound in each well (%) wascalculated based on the values of enzyme-free well and inhibitor-freewell. The inhibitory activity of the compound was represented as IC₅₀(μM)

EXPERIMENTAL EXAMPLE 3

Inhibitory activity of tested compounds on MMP-13 was measured usingMMP-13 specific fluorescent substrate with quencher.

The enzyme and substrate were diluted with Tris-HCl buffer, and testcompounds were diluted with dimethyl sulfoxide (DMSO).

Test compounds and the enzyme (Recombinant Human MMP-13: R&D systems,511-MM) were added into 96-well plate. The reaction was initiated byadding synthetic substrate (7-MCA-Pro-CHA-Gly-NVal-His-Ala-DPA: enzymesystems products, Met-06) into the plate. After incubation at 25° C. for1 h, the reaction was terminated by addition of reaction terminatingsolution containing acetic acid. Fluorescence intensity of each well wasmeasured (Ex: 325 nm, Em: 405 nm) and the MMP-13 inhibitory activity ofthe compound in each well (%) was calculated based on the values ofenzyme-free well and inhibitor-free well. The inhibitory activity of thecompound was represented as IC₅₀ (μM).

The results of the aforementioned Experimental Examples 1 to 3 are shownin Tables 3-1 to 3-19. In the table, + means less than 1 μM, ++ meansless than 0.1 μM, − means not less than 1 μM, −− means not less than 10μM and blank column means “not tested”.

TABLE 3-1 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 1 + − 1-2 ++ − ++ 1-3 ++− ++ 1-4 ++ − 1-7 + −− 1-10 + − + 1-11 + − + 1-12 + − ++ 1-13 + − 1-14 +−− 1-16 + − ++ 1-18 + − ++ 1-21 + − 1-26 + −− + 1-31 + −− 1-38 ++ −− ++1-40 + − ++ 1-41 + − ++ 1-42 + − 1-43 + − 1-44 + − 1-54 + − + 1-61 + −++ 1-62 + − ++ 1-63 + − ++ 1-64 + − ++ 1-65 −− 1-66 + − ++ 1-68 + − ++1-69 ++ −− + 1-72 ++ − + 1-74 + − ++ 1-75 + − ++ 1-76 + −− ++ 1-80 ++ −−1-83 + − ++ 1-84 + −− + 1-85 ++ − ++ 1-86 + − + 1-88 ++ −− + 1-90 + − ++

TABLE 3-2 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 1-91 ++ − ++ 1-94 ++ −++ 1-98 + −− 1-100 + − 1-101 + −− 1-102 ++ − + 1-103 + −− + 1-104 + −−1-105 + − 1-107 ++ − ++ 1-108 ++ − ++ 1-109 + −− + 1-110 + − 1-112 + −1-113 ++ − + 1-114 + − 1-115 + − 1-116 + − 1-117 ++ − 1-118 ++ − 1-119++ − ++ 1-121 ++ − ++ 1-122 ++ − ++ 1-125 ++ −− 1-127 ++ − + 1-128 ++− + 1-129 ++ − ++ 1-130 ++ − ++ 1-131 ++ − ++ 1-132 ++ − ++ 1-133 ++ −++ 1-134 ++ − ++ 1-135 + − 1-136 ++ − ++ 1-137 + − 1-138 ++ − + 1-139 ++−− + 1-145 + −− 1-146 ++ −− 1-147 + −−

TABLE 3-3 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2 − −− −− 2-2 −− −− −−2-3 − −− − 2-4 ++ + ++ 2-5 + − ++ 2-6 ++ − + 2-7 ++ + ++ 2-8 ++ − ++ 2-9++ ++ ++ 2-10 ++ + ++ 2-11 − − − 2-12 ++ + ++ 2-13 ++ −− ++ 2-14 −− −−−− 2-15 −− −− − 2-16 −− −− + 2-17 − −− ++ 2-18 + − + 2-19 + −− + 2-20 +− ++ 2-21 + − + 2-22 ++ −− ++ 2-23 + −− + 2-24 + −− + 2-25 ++ −− +2-26 + −− 2-27 + −− + 2-28 − −− 2-29 − ++ 2-30 − − 2-31 − − 2-32 ++ −−++ 2-33 − + 2-34 − + 2-35 + −− + 2-36 + −− + 2-37 ++ −− ++ 2-38 − +

TABLE 3-4 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2-39 + − ++ 2-40 + −− +2-41 + −− + 2-42 ++ −− ++ 2-43 ++ + ++ 2-44 − −− − 2-45 − −− − 2-46 − −−− 2-47 − −− + 2-48 + −− − 2-49 − −− −− 2-50 − −− − 2-51 − −− − 2-52 +−− + 2-53 − −− − 2-54 − −− −− 2-55 − −− −− 2-56 ++ −− ++ 2-57 + −− ++2-58 + −− + 2-59 + −− + 2-60 −− −− − 2-61 + −− + 2-62 + −− + 2-63 ++ −++ 2-64 −− −− − 2-65 + −− + 2-66 − −− − 2-67 −− −− + 2-68 − −− ++ 2-69++ − ++ 2-70 + −− 2-71 ++ −− + 2-72 ++ −− + 2-73 ++ −− + 2-74 + −− ++2-75 + −− + 2-76 ++ −− +

TABLE 3-5 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2-77 ++ − + 2-78 ++ −− +2-79 −− −− −− 2-80 −− −− −− 2-81 −− −− −− 2-82 −− −− −− 2-83 −− −− −−2-84 ++ + ++ 2-85 + − ++ 2-86 ++ −− + 2-87 −− −− − 2-88 −− −− −− 2-89 −−− − 2-90 − − ++ 2-91 + −− + 2-92 ++ + ++ 2-93 −− −− − 2-94 −− −− −−2-95 −− −− −− 2-96 −− −− + 2-97 −− −− −− 2-98 ++ − ++ 2-99 ++ + + 2-100++ + ++ 2-101 ++ − + 2-102 + + 2-103 −− −− −− 2-104 −− −− −− 2-105 −− −−−− 2-106 −− −− −− 2-107 ++ + ++ 2-108 ++ − ++ 2-109 ++ −− ++ 2-110 + −++ 2-111 − −− + 2-112 + −− − 2-113 ++ + ++ 2-114 − + ++

TABLE 3-6 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2-115 − + 2-116 −− −− −−2-117 −− −− −− 2-118 − − 2-119 ++ + ++ 2-120 ++ + ++ 2-121 ++ + ++ 2-122− + 2-123 + −− + 2-124 ++ − ++ 2-125 −− −− −− 2-126 −− −− −− 2-127 −− −−2-128 −− −− −− 2-129 + −− + 2-130 − −− − 2-131 ++ − + 2-132 −− −− −−2-133 −− −− + 2-134 −− −− + 2-135 − ++ 2-136 + − ++ 2-137 − + ++ 2-138−− 2-139 − −− − 2-140 −− −− − 2-141 + − ++ 2-142 ++ − + 2-143 −− −− −2-144 −− −− − 2-145 −− −− − 2-146 + −− + 2-147 − −− − 2-148 − −− + 2-149− −− ++ 2-150 + − + 2-151 −− −− − 2-152 + −− ++

TABLE 3-7 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2-153 −− −− − 2-154 −−− + 2-155 − −− + 2-156 − −− − 2-157 −− −− − 2-158 −− −− −− 2-159 −− −−−− 2-160 −− −− −− 2-161 −− −− − 2-162 −− −− −− 2-163 −− −− −− 2-164 −−−− −− 2-165 −− −− − 2-166 −− −− −− 2-167 + −− 2-168 + −− − 2-169 ++ − ++2-170 ++ −− ++ 2-171 + −− + 2-172 −− −− − 2-173 ++ − ++ 2-174 ++ − ++2-175 ++ − + 2-176 ++ −− ++ 2-177 − −− − 2-178 ++ −− + 2-179 ++ −− +2-180 ++ −− ++ 2-181 ++ − ++ 2-182 ++ −− ++ 2-183 ++ − ++ 2-184 ++ − +2-185 − −− + 2-186 − −− − 2-187 −− −− −− 2-188 ++ − ++ 2-189 ++ −− ++2-190 ++ − ++

TABLE 3-8 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2-191 ++ −− ++ 2-192 +−− + 2-193 + −− + 2-194 + −− + 2-195 + −− + 2-196 ++ − ++ 2-197 + −− +2-198 + −− + 2-199 + −− + 2-200 + −− + 2-201 + −− ++ 2-202 + −− +2-203 + −− ++ 2-204 ++ −− + 2-205 ++ −− + 2-206 ++ − ++ 2-207 + −− +2-208 ++ − ++ 2-209 ++ − ++ 2-210 + −− ++ 2-211 ++ −− ++ 2-212 ++ − +2-213 ++ + ++ 2-214 ++ + ++ 2-215 ++ −− + 2-216 + −− + 2-217 + −− +2-218 − −− 2-219 + − ++ 2-220 ++ − ++ 2-221 + − ++ 2-222 ++ − ++ 2-223 +−− + 2-224 ++ − ++ 2-225 − −− + 2-226 + −− + 2-227 ++ − + 2-228 + − +

TABLE 3-9 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2-229 + −− + 2-230 + −−++ 2-231 + − ++ 2-232 + − ++ 2-233 + − ++ 2-234 ++ − ++ 2-235 + − ++2-236 + − ++ 2-237 ++ − ++ 2-238 + − ++ 2-239 ++ − ++ 2-240 + − +2-241 + − ++ 2-242 ++ − ++ 2-243 + − ++ 2-244 + −− + 2-245 − −− + 2-246− −− + 2-247 −− −− −− 2-248 ++ − + 2-249 ++ −− + 2-250 + − ++ 2-251 +−− + 2-252 ++ − + 2-253 ++ − ++ 2-254 ++ − ++ 2-255 ++ − ++ 2-256 − −−−− 2-257 ++ − + 2-258 + − + 2-259 ++ − ++ 2-260 + − ++ 2-261 + −− +2-262 ++ + ++ 2-263 ++ − + 2-264 ++ − ++ 2-265 + −− + 2-266 + − +

TABLE 3-10 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2-267 ++ − ++ 2-268 ++ −++ 2-269 ++ − ++ 2-270 ++ − ++ 2-271 − −− + 2-272 ++ −− ++ 2-273 ++ + ++2-274 ++ −− − 2-275 ++ − + 2-276 + − ++ 2-277 + − + 2-278 ++ + ++ 2-279++ + ++ 2-280 + −− ++ 2-281 ++ + ++ 2-282 ++ + ++ 2-283 + − ++ 2-284 ++− ++ 2-285 + − − 2-286 ++ − ++ 2-287 ++ + ++ 2-288 ++ + ++ 2-289 + − +2-290 ++ + ++ 2-291 ++ + ++ 2-292 ++ + ++ 2-293 ++ + ++ 2-294 ++ − ++2-295 ++ − ++ 2-296 − −− − 2-297 − −− − 2-298 ++ − ++ 2-299 ++ ++ ++2-300 + − ++ 2-301 ++ − ++ 2-302 ++ + ++ 2-303 ++ − ++ 2-304 + − +

TABLE 3-11 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2-305 ++ − ++ 2-306 +− + 2-307 − −− − 2-308 + − + 2-309 + − + 2-310 + + ++ 2-311 + − + 2-312− −− −− 2-313 + − + 2-314 − −− −− 2-315 + −− + 2-316 − −− −− 2-317 + − +2-318 − −− −− 2-319 ++ − ++ 2-320 + − + 2-321 + − + 2-322 ++ − + 2-323 −− ++ 2-324 − −− − 2-325 − −− − 2-326 + − + 2-327 + + ++ 2-328 ++ ++ ++2-329 − −− − 2-330 − −− − 2-331 + − + 2-332 + − + 2-333 + − + 2-334 +− + 2-335 + − + 2-336 − −− − 2-337 + −− + 2-338 ++ − + 2-339 ++ − +2-340 + −− − 2-341 ++ −− − 2-342 + − −

TABLE 3-12 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2-343 − −− − 2-344 ++−− + 2-345 ++ −− + 2-346 + −− + 2-347 ++ −− + 2-348 + −− + 2-349 ++ −− +2-350 + − ++ 2-351 ++ + ++ 2-352 ++ − ++ 2-353 ++ + ++ 2-354 ++ − +2-355 − − + 2-356 + + + 2-357 ++ − ++ 2-358 ++ − + 2-359 + − ++ 2-360 ++−− + 2-361 − −− − 2-362 + −− ++ 2-363 − −− + 2-364 + + ++ 2-365 ++ + ++2-366 ++ + ++ 2-367 − −− − 2-368 + − + 2-369 ++ − ++ 2-370 ++ + ++ 2-371− −− − 2-372 − −− − 2-373 − −− − 2-374 ++ + ++ 2-375 ++ + ++ 2-376 +−− + 2-377 + − + 2-378 + − + 2-379 + − + 2-380 + −− +

TABLE 3-13 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2-381 + −− + 2-382++ + + 2-383 ++ + ++ 2-384 + −− ++ 2-385 + −− + 2-386 + − + 2-387 − −− +2-388 + − + 2-389 ++ − ++ 2-390 + −− − 2-391 − −− + 2-392 − −− − 2-393 +− ++ 2-394 + − ++ 2-395 + −− + 2-396 + −− + 2-397 + −− + 2-398 + −− +2-399 + − + 2-400 − − + 2-401 ++ + ++ 2-402 − −− 2-403 + + ++ 2-404 ++ +++ 2-405 ++ −− + 2-406 ++ + ++ 2-407 ++ + ++ 2-408 ++ + ++ 2-409 + + ++2-410 ++ − − 2-411 ++ + ++ 2-412 ++ − ++ 2-413 ++ − + 2-414 + − + 2-415− −− 2-416 + − + 2-417 + − 2-418 − −

TABLE 3-14 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2-419 ++ + ++ 2-420 − −−− 2-421 − −− − 2-422 ++ + + 2-423 + + ++ 2-424 −− + + 2-425 −− −− −2-426 + − ++ 2-427 −− + − 2-428 + − ++ 2-429 + − + 2-430 ++ − ++ 2-431 +− + 2-432 ++ − + 2-433 ++ + ++ 2-434 ++ − + 2-435 ++ + ++ 2-436 − −− −2-437 ++ + ++ 2-438 ++ + ++ 2-439 ++ − ++ 2-440 + −− + 2-441 ++ − ++2-442 − −− − 2-443 − −− − 2-444 ++ + ++ 2-445 + −− + 2-446 − −− −2-447 + + ++ 2-448 − −− − 2-449 ++ − ++ 2-450 + −− + 2-451 − −− −2-452 + + ++ 2-453 − −− + 2-454 + −− − 2-455 − − 2-456 − −

TABLE 3-15 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2-457 ++ − ++ 2-458 + −−++ 2-459 + − ++ 2-460 + − ++ 2-461 + −− − 2-462 + − − 2-463 − −− − 2-464− −− − 2-465 − −− −− 2-466 + − − 2-467 − −− −− 2-468 + − 2-469 − −−2-470 ++ + ++ 2-471 − −− − 2-472 + − −− 2-473 − −− − 2-474 − −− − 2-475− −− − 2-476 − −− −− 2-477 − −− − 2-478 − −− −− 2-479 − −− −− 2-480 + +++ 2-481 − −− ++ 2-482 − −− ++ 2-483 − −− − 2-484 − −− + 2-485 + −− −2-486 + + ++ 2-487 − −− − 2-488 − −− − 2-489 − −− ++ 2-490 − −− ++ 2-491− −− ++ 2-492 ++ ++ ++ 2-493 ++ + ++ 2-494 ++ ++ ++

TABLE 3-16 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2-495 ++ ++ ++ 2-496++ + ++ 2-497 ++ − ++ 2-498 ++ − + 2-499 + + ++ 2-500 − − + 2-501 − − −2-502 − − − 2-503 + − + 2-504 − − + 2-505 − − + 2-506 − + ++ 2-507 − +++ 2-508 − − − 2-509 + − ++ 2-510 − − − 2-511 − − − 2-512 − − − 2-513 −− − 2-514 + − + 2-515 − − − 2-516 + − + 2-517 ++ − + 2-518 + + ++ 2-519− − − 2-520 − − − 2-521 + − ++ 2-522 − − ++ 2-523 + + ++ 2-524 ++ ++ ++2-525 ++ ++ ++ 2-526 − − − 2-527 − − − 2-528 − − − 2-529 − − − 2-530 − −− 2-531 − − − 2-532 − − −

TABLE 3-17 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2-533 − − − 2-534 − − −2-535 − − − 2-536 − − − 2-537 − − − 2-538 − − + 2-539 ++ + ++ 2-540 −− + 2-541 − − − 2-542 + − ++ 2-543 ++ ++ ++ 2-544 + − + 2-545 ++ ++ ++2-546 ++ ++ ++ 2-547 ++ ++ ++ 2-548 − − − 2-549 − − − 2-550 − − − 2-551− − − 2-552 − − + 2-553 − − − 2-554 − − + 2-555 + − + 2-556 − − ++2-557 + − ++ 2-558 − − + 2-559 ++ − + 2-560 + − + 2-561 ++ ++ ++ 2-562 −− − 2-563 − − − 2-564 ++ − ++ 2-565 ++ + ++ 2-566 + − − 2-567 ++ − +2-568 ++ + ++ 2-569 ++ + ++ 2-570 + − ++

TABLE 3-18 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2-571 − − + 2-572 ++ −++ 2-573 + − ++ 2-574 + + ++ 2-575 − 2-576 − 2-577 ++ + ++ 2-578 + − ++2-579 ++ + ++ 2-580 + − ++ 2-581 ++ − + 2-582 + − + 2-583 − − 2-584 + −++ 2-585 − − 2-586 − −− 2-587 − − + 2-588 ++ + + 2-589 + − − 2-590 ++ −++ 2-591 − − ++ 2-592 − 2-593 + − + 2-594 + − + 2-595 − − ++ 2-596 + − +2-597 − − −− 2-598 ++ − + 2-599 ++ − + 2-600 + − + 2-601 + − − 2-602++ + + 2-603 + + + 2-604 + − 2-605 − −− − 2-606 − −− − 2-607 − − ++2-608 ++ + +

TABLE 3-19 Experimental Experimental Experimental Example 1 Example 2Example 3 Example IC₅₀ AG1 IC₅₀ MMP1 IC₅₀ MMP13 2-609 ++ ++ ++ 2-610++ + − 2-611 ++ + − 2-612 ++ + − 2-613 ++ + − 2-614 ++ + − 2-615 ++ ++++ 2-616 ++ + + 2-617 + − − 2-618 ++ + + 2-619 ++ + + 2-620 ++ + ++2-621 ++ + ++ 2-622 − − + 2-623 ++ + ++ 2-624 ++ 2-625 ++

The compound (1) of the present invention described in the results abovehas superior aggrecanase inhibitory activity and MMP-13 inhibitoryactivity, and high selectivity to aggrecanase as compared to theactivity of MMP-1.

INDUSTRIAL APPLICABILITY

According to the present invention, a compound useful as a prophylacticor therapeutic agent for diseases mediated by aggrecanase, such asosteoarthritis (OA), rheumatoid arthritis (RA), joint injury, reactivearthritis, cancer, asthma, allergic reaction, chronic pulmonaryemphysema, fibroid lung, acute respiratory distress (ARDS), lunginfection, interstitial pneumonia, bone resorption disorder, etc. isprovided.

1. A cyclopropane compound of formula (1):

wherein R¹ is selected from (1) a substituted C₁₋₆ alkyl group and (2)—(CH₂)_(m)—X—(CH₂)_(n)-A¹, wherein m and n are the same or different andeach is selected from 0 and an integer ranging from 1 to 6, X is alinker selected from the following group A, group A: (a) a single bond,(b) a C₁₋₆ alkylene group, (c) a C₂₋₆ alkenylene group, (d) a C₂₋₆alkynylene group, (e) —O—, (f) —N(R⁵)—, (g) —S(O)_(m1)—, (h) —CO—, (i)—COO—, (j) —OCO—, (k) —CON(R⁵)—, (l) —N(R⁵)CO—, (m) —SO₂N(R⁵)—, (n)—N(R⁵)SO₂—, (o) —N(R⁵)CON(R⁶)—, (p) —N(R⁵)SO₂N(R⁶)—, (q) —OCON(R⁵)—, (r)—N(R⁵)COO—, and (s) —S(O)_(m1)—(CH₂)_(n1)—CO—; wherein R⁵ and R⁶ are thesame or different and each is selected from a hydrogen atom, a C₁₋₆alkyl group optionally substituted by halogen atoms or hydroxyl groups,a C₃₋₁₄ hydrocarbon ring group and a heterocyclic group, m1 is selectedfrom 0 and an integer ranging from 1 to 2 and n1 is selected from aninteger ranging from 1 to 2, and A¹ is selected from a substituted C₃₋₁₄hydrocarbon ring group and a substituted heterocyclic group; R² and R³are the same or different and each is selected from (1)—(CH₂)_(p)—X₁—(CH₂)_(q)-A², wherein p and q are the same or differentand each is selected from 0 and an integer ranging from 1 to 6, X₁ is alinker selected from the above-mentioned group A and A² is selected froman optionally substituted C₃₋₁₄ hydrocarbon ring group and an optionallysubstituted heterocyclic group, and (2) —(CH₂)_(m8)—X₈—(CH₂)_(n8)—R²⁷,wherein m8 and n8 are the same or different and each is selected from 0and an integer ranging from 1 to 6, X₈ is a linker selected from theabove-mentioned group A and R²⁷ is a substituent selected from thefollowing group B, group B: (a) a hydrogen atom, (b) a halogen atom, (c)a hydroxyl group, (d) a nitro group, (e) a cyano group, (f) a carboxylgroup, (g) an amino group, (h) an amido group, (i) a C₂₋₆ acyl group,(j) a halogenated C₁₋₆ alkyl group, (k) a C₁₋₆ alkyl group optionallysubstituted by hydroxyl groups, (l) a C₂₋₆ alkenyl group optionallysubstituted by halogen atoms, (m) a C₂₋₆ alkynyl group, (n) a C₁₋₆alkoxy group optionally substituted by hydroxyl groups, (o) a C₁₋₆alkoxy-C₁₋₆ alkyl group, (p) a C₁₋₆ alkoxy-carbonyl group, (q) a C₁₋₆alkyl-aminocarbonyl group optionally substituted by halogen atoms, (r) amono(C₁₋₆ alkyl)amino group, (s) a di(C₁₋₆ alkyl)amino group, (t) a C₁₋₆alkyl-carbonylamino group optionally substituted by halogen atoms, (u) aC₁₋₆ alkylsulfonyl group, and (v) a C₁₋₆ alkylsulfonylamino group; or A²and R²⁷ may be taken together to form an optionally substituted fusedring group, or R² and R³ may be taken together with a carbon atom bondedthereto to form the following ring

wherein m13 is selected from an integer ranging from 1 to 6, providedthat R² and R³ are not hydrogen atoms at the same time; R⁴ is selectedfrom (1) —CO₂R⁹, (2) —C(O)NHOR⁹, (3) —C(O)NH—SO₂—R⁹, (4) —C(O)NHR⁹, (5)—SH, (6) —CH₂CO₂R⁹, (7) —C(O)R⁹, (8) —N(OH)COR⁹, (9) —SN₂H₂R⁹, (10)—SONHR⁹, (11) —CH₂CO₂H, (12) —PO(OH)₂, (13) —PO(OH)NHR⁹, (14) —CH₂SH,(15) —CH₂OH, (16) —(CH₂)_(r1)—PO(OH)—(CH₂)_(r2)—R⁹, (17) —NHR⁹, (18)—NH—NHR⁹, and (19) —(CH₂)_(r1)—R⁵⁰; wherein r1 and r2 are the same ordifferent and each is selected from 0 and an integer ranging from 1 to6, R⁹ is selected from (1) a hydrogen atom, (2) an optionallysubstituted C¹⁻¹⁰ alkyl group, (3) an optionally substituted C₆₋₁₄aryl-C₁₋₆ alkyl groups and (4) —(CH₂)_(m9)—X₉—(CH₂)_(n9)—R²⁸; wherein m9and n9 are the same or different and each is selected from 0 and aninteger ranging from 1 to 6, X₉ is a linker selected from theabove-mentioned group A and R²⁸ is a substituent selected from thefollowing group C, group C: (a) a hydrogen atom, (b) a halogen atom, (c)a hydroxyl group, (d) a nitro group, (e) a cyano group, (f) a carboxylgroup, (g) an amino group, (h) an amido group, (i) a C₂₋₆ acyl group,(j) a halogenated C₁₋₆ alkyl group, (k) a C₁₋₆ alkyl group optionallysubstituted by hydroxyl groups, (l) a C₂₋₆ alkenyl group optionallysubstituted by halogen atoms, (m) a C₂₋₆ alkynyl group, (n) a C₁₋₆alkoxy group optionally substituted by hydroxyl groups, (o) a C₁₋₆alkoxy-C₁₋₆ alkyl group, (p) a C₁₋₆ alkoxy-carbonyl group, (q) a C₁₋₆alkyl-aminocarbonyl group optionally substituted by halogen atoms, (r) amono(C₁₋₆ alkyl)amino group, (s) a di(C₁₋₆ alkyl)amino group, (t) a C₁₋₆alkyl-carbonylamino group optionally substituted by halogen atoms, (u) aC₁₋₆ alkylsulfonyl group, (v) a C₁₋₆ alkylsulfonylamino group, (w) aC₃₋₁₄ hydrocarbon ring group optionally substituted by 1 to 5substituent(s) selected from the above-mentioned group B, and (x) aheterocyclic group optionally substituted by 1 to 5 substituent(s)selected from the above-mentioned group B, and R⁵⁰ is selected from anoptionally substituted C₃₋₁₄ hydrocarbon ring group and an optionallysubstituted heterocyclic group; or R⁹ of —C(O)NHR⁹, A² and thecyclopropane ring may be taken together to form an optionally furthersubstituted fused ring; R²⁰ and R²¹ are the same or different and eachis selected from (1) —(CH₂)_(m10)—X₁₀—(CH₂)_(n10)-A³, wherein m10 andn10 are the same or different and each is selected from 0 and an integerranging from 1 to 6, X₁₀ is a linker selected from the above-mentionedgroup A and A³ is selected from an optionally substituted C₃₋₁₄hydrocarbon ring group and an optionally substituted heterocyclic group,and (2) —(CH₂)_(m12)—X₁₂—(CH₂)_(n12)—R³⁰, wherein m12 and n12 are thesame or different and each is selected from 0 and an integer rangingfrom 1 to 6, X₁₂ is a linker selected from the above-mentioned group Aand R³⁰ is a substituent selected from the above-mentioned group B; orA², R³⁰ and the cyclopropane ring may be taken together to form aoptionally further substituted fused ring, or R⁹ of —CO₂R⁹, R²⁰ and thecyclopropane ring may be taken together to form an optionally furthersubstituted fused ring, or R²⁰ and R²¹ may be taken together with acarbon atom bonded thereto to form the following ring

wherein m14 is selected from an integer ranging from 1 to 6; or apharmaceutically acceptable salt thereof. 2-34. (canceled)